Scott A Rivkees
Yale University
Project start date: 2010-05-01
Project end date: 2014-04-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Scott A Rivkees
A-1 Adenosine Receptor Action In Developing Heart
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R01HL058442-08 from National Heart, Lung, And Blood Institute IRG: HED
Abstract: We completed our original Specific Aims directed at studying the effects of Al adenosine receptor (A1AR) activation on the developing heart. We found that adenosine is the dominant humoral regulator of embryonic cardiac function, that early A1AR expression results from NKX2.5 and GATA4 activation of the A1AR promoter, and that A1AR activation inhibits cardiac cell division leading to cardiac hypoplasia. We also expanded our studies to examine cardiac effector systems during early heart formation. In the course of these experiments we found that Rho GTPase signaling plays a very important role in heart formation. In this competitive renewal, we will focus on the influence of Rho GTPase activity on mammalian cardiac development and the regulation of Rho activity by receptors for adenosine and other neuromodulators. GTPases are small intracellular signaling molecules that transduce the effects of extracellular signals and include Rho, which activates Rho-associated kinase (ROCK) to influence important cellular events. Recent evidence suggests that these factors play essential roles in the mature myocardium. Yet, their role in heart development is not known. Suggesting that GTPases are important in heart formation, we found that blockade of the Rho/ROCK effector system leads to major cardiac malformations. Thus, we hypothesize that Rho GTPases play a critical role in heart formation. We also hypothesize that cardiac Rho/ROCK activity is regulated by G protein-coupled receptors (GPCRs) during early developmental stages. To test these hypotheses and provide insights into the role of GTPases in the developing heart, the following Specific Aims are proposed. (1) We will characterize the temporal and spatial patterns of Rho/ROCK expression during embryogenesis. (2) We will examine the effects of Rho/ROCK signaling on heart development. (3) We will examine mechanisms by which Rho/ROCK action effects heart development. (4) We will examine GPCR regulation of Rho/ROCK activity in the embryonic heart. These experiments will build on the experience we acquired in studying the effects of adenosine on the developing heart. We anticipate that these studies will identify Rho and ROCK as critical signaling molecules in heart development and reveal that cardiac GTPase activity transduces the effects of adenosine.
Keywords: embryogenesis, guanine nucleotide binding protein, guanosinetriphosphatase, histogenesis, myocardium, purinergic receptor, G protein, G protein coupled receptor kinase, angiogenesis, biological signal transduction, cardiac myocyte, enzyme activity, gene expression, heart function, receptor coupling, receptor expression, embryo /fetus culture, genetically modified animal, histology, laboratory mouse, laboratory rat, tissue /cell culture
Project start date: 1997-08-15
Project end date: 2006-11-30
5R01HL058442-08 (2005): $327000
5R01HL058442-07 (2004): $327000
5R01HL058442-06 (2003): $327000
Newborn Screening For Sex Chromosome Disorders
Scott A Rivkees, Professor
Js Genetics, Llc 397 Post Road, Suite 203 Darien, Ct 06820
Grant 1R41HD049230-01A1 from National Institute Of Child Health And Human Development IRG: ZRG1
Abstract: Turner syndrome (TS) is the most common genetic problem effecting women, with an incidence of 1 in 1,500 to 2,000 live female births and occurs when an entire, or portions of an X-chromosome is deleted. Phenotypic features include primary hypogonadism, renal abnormalities, and profound short stature. Yet, with growth hormone therapy, acceptable adult stature can be achieved. Currently, many girls with TS are diagnosed after 10 years of age. Thus recognition of cardiac, renal, and learning problems may be delayed, and final height may be compromised. Girls with TS are also at risk for gonadal tumor development if Y-chromosomal is present. Recently we developed a strategy to screen for Tuner syndrome and other sex chromosome abnormalities that relies on genomic DNA screening using informative single nucleotide polymorphism (SNP) markers that span the X and Y-chromosomes. This is followed by quantitative assessment of allele, signal strength from single nucleotides via pyrosequencing. Thus, we propose to develop an effective, low-cost newborn screening test (the sex chromosome disorder screening test) for detecting TS with commercial application. Our Phasel milestones will be to (1) test for and optimize assay sensitivity and accuracy, (2) test for selectivity (rate of false-positives). (3) Create multiplex marker sets to minimize cost. We anticipate that this Phase 1 application will lead to the development of an assay that is suitable for high-throughput population screening for sex chromosome disorders. In next steps, we anticipate submitting a Phase 2 application for piloting large-scale newborn screening studies. If successful, this strategy will be applicable to the 2 million female infants born each year in the United States tested by state newborn screening programs, and to the several hundred thousand infants tested by commercial newborn screening services.
Keywords: Turner s syndrome, chromosome aberration, developmental genetics, diagnosis design /evaluation, early diagnosis, genetic marker, genetic screening, newborn human (0-6 weeks), sex chromosome, single nucleotide polymorphism, chromosome disorder, cost effectiveness, diagnosis quality /standard, sex linked trait, biotechnology, cell line, high throughput technology
Project start date: 2006-03-23
Project end date: 2007-08-31
1R41HD049230-01A1 (2006): $129953
CB1 Receptor Action On The Developing Hippocampus
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R21DA019344-02 from National Institute On Drug Abuse IRG: ZDA1
Abstract: Several adverse effects of marijuana (cannabis) use are recognized including those on central nervous system function. Among the most prominent effects of cannabis on neural function are deleterious influences on memory, which may be related to damage to the hippocampus. In the brain, the effects of cannabinoids are transduced by the CB1 receptor (CB1R). CB1Rs are highly expressed during development, couple with Gi/Go, inhibit neurotransmitter release, and hyperpolarize neurons. Whereas a considerable amount of information is known about cannabis and CB1R action in the mature nervous system, relatively little is known about effects on the developing brain. Increasing evidence suggests that suppression of neuronal activity during critical periods of brain growth will trigger neuronal apoptosis. Suggesting that the developing brain is also sensitive to effects of CB1R activation, we observe that acute cannabinoid exposure induces apoptosis in the developing, but not mature hippocampus. Based on these observations, we propose to test the hypotheses that (1) the developing hippocampus is especially sensitive to the effects of CB1R activation. (2) Cannabinoid toxicity during early development is due to inhibition of neuronal activity. To test these hypotheses we will perform in vivo and in vitro studies using contemporary neuroscience methods and CB1R knock-out mice. We anticipate that these studies will result in new insights into the potential effects of cannabinoid action on the developing brain.
Keywords: cannabinoid receptor, developmental neurobiology, hippocampus, neurotoxicology, protein structure function, receptor expression, apoptosis, brain injury, glutamate, neural degeneration, neurotransmitter transport, genetically modified animal, laboratory mouse, terminal nick end labeling, tissue /cell culture
Project start date: 2004-09-24
Project end date: 2006-07-31
5R21DA019344-02 (2005): $204375
1R21DA019344-01 (2004): $245250
DEVELOPING CIRCADIAN RHYTHMICITY
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R01NS032624-05 from National Institute Of Neurological Disorders And Stroke IRG: NEUB
Abstract: In mammals, the circadian system influences many physiologic processes. During development, the circadian system may influence neonatal growth and behavior, and may play a role in the pathogenesis of illnesses including Sudden Infant Death Syndrome. In contrast to what is known in rodents, little is known about the development and function of the circadian timing system in primates. This application represents a focused effort using physiological, molecular and biochemical approaches to characterize the development of the circadian system in a primate. The hypothalamic suprachiasmatic nuclei (SCN) are the site of a biological clock generating and regulating numerous circadian rhythms. In placental mammals, the SCN begin oscillating in utero. Before the SCN are innervated by the retina, the mother regulates (entrains) the oscillations of the fetal clock. Some time after innervation of the SCN by the retina, the light-dark cycle regulates clock activity. For several reasons, it is not feasible to use humans or other non- primate species for these proposed developmental studies. Baboons (Papio species) are excellent models of human development, and as such, will be used in the proposed experiments. First, using histologic and receptor localization methods, we will examine the anatomical development of the SCN. Second, using the [14C]-deoxyglucose method, we will determine when the fetal SCN begin to oscillate. Third, we will characterize the development of physical and humoral circadian rhythms in term and preterm animals. Fourth, we will use biochemical methods to determine the onset of photic responsiveness and examine molecular responses to light in the SCN. Fifth, we will examine how light regulates the timing of the developing clock. Many physiologic activities and pathologic processes are synchronized with the daily light-dark cycle. Understanding the development of circadian rhythmicity in primates will better allow us to understand neonatal physiology and environmental influences on the developing infant.
Keywords: circadian rhythm, developmental neurobiology, growth /development, suprachiasmatic nucleus, hormone receptor, melatonin, nonvisual photosensitivity, oxytocin, photobiology, receptor expression, vasopressin, autoradiography, baboon, carbon, deoxyglucose, histology, in situ hybridization, radionuclide, telemetry
Project start date: 1994-12-01
Project end date: 1999-06-30
5R01NS032624-05 (1998): $320734
5R01NS032624-04 (1997): $308398
GRAVES´ DISEASE THERAPY RISKS TO MOTHER AND FETUS
Scott A Rivkees
Yale University, 47 College Street, Ste 203, New Haven, Ct 06520-8047
Grant 1R01HD065200-01A1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Graves´ disease (GD) accounts for the vast majority of cases of hyperthyroidism in young adults. It is estimated that there are 30,000 women of childbearing age with GD in the United States (US), and that 4,000 to 8,000 women are treated for GD during pregnancy annually. Antithyroid drug (ATD) therapy is the recommended treatment of GD during pregnancy. Based on observations of birth defects (aplasia cutis and choanal atresia) in offspring of mothers treated with MMI during pregnancy, and the absence of such reports related to PTU use, PTU has been recommended as the drug-of-choice for pregnant women with GD. In preliminary studies, in US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we discovered a substantial number of major birth defects in the offspring of women treated with PTU during pregnancy. In our analysis of International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) data, we observed birth defects with PTU (congenital heart defects) and MMI (choanal atresia, omphalocelle) use during pregnancy. In murine models, we observed that PTU exposure during embryogenesis (E7.5 to 10.5) is associated with skull and cardiac defects, whereas we do not observe malformations in embryos of dams treated with MMI or high doses of levo-thyroxine (LT4). These observations suggest that current recommendations for the treatment of GD during pregnancy with ATDs may not be optimal. Considering the above data, we hypothesize that (1) PTU use during pregnancy is associated with a risk of major birth defects. (2) The nature of birth defects associated with hyperthyroidism, PTU and MMI use during pregnancy differ in type and incidence. (3) Hyperthyroidism itself may contribute to birth defects during pregnancy. (4) There is a risk of liver injury to pregnant mothers during pregnancy associated with PTU use. To test these hypotheses, two specific aims are proposed Specific Aim 1 Assess the risks of ATD treatment during pregnancy on mother and fetus. Cohort studies will be performed using large clinical databases, including those of Marketscan (>1.2 million pregnancies) and Kaiser Permanente Northern California (KPNC; (>300,000 pregnancies). Databases will be analyzed to assess the prevalence of GD in pregnancy, ATD treatment use in pregnant women with GD, co-morbid conditions (i.e., liver disease) associated with GD and ATD use in pregnancy, and birth defects and other co-morbid conditions in infants born to mothers with GD and treated with ATDs. Specific Aim 2 Assess teratogenic potential of PTU and MMI. To complement human cohort studies, we will perform basic teratogenicity studies to assess the birth defect risks of PTU and MMI. We will examine effects on fetal viability, growth and morphology, as related to drug dose. We will define periods of vulnerability of the embryo to affects of PTU and MMI. We will examine the contribution of the hyperthyroid state to birth defects. We will use methods and a testing laboratory that satisfies requirements of the FDA. These studies will involve collaborative efforts with Dr. James Korelitz (Westat), who is an expert in database interrogation; Dr. Joan C. Lo, M.D. (Kaiser Permanente), who is an expert in endocrinology and database analysis; Dr. Alan Hoberman (Charles River Laboratory), who is an expert in teratogenicity testing and Dr. Scott Rivkees (Yale University) who is an expert in developmental biology and thyroid disorders. It is anticipated that these studies will provide new insights into the risks involved with ATD treatment of GD during pregnancy. When completed, we anticipate that these studies will provide needed epidemiology and basic-teratology data about the relative risks of PTU, MMI, and hyperthyroidism to mother and fetus. The goal of these studies is to determine the risks of antithyroid drug therapy during pregnancy on mother and fetus. When completed, we anticipate that these studies will provide needed epidemiology and basic-teratology data about the relative risks of PTU, MMI, and hyperthyroidism to mother and fetus
Keywords: 0-11 years old; 1-Methyl-2-mercaptoimidazole; 21+ years old; 2H-Imidazole-2-thione, 1, 3-dihydro-1-methyl-; 3, 5, 3`, 5`-Tetraiodothyronine; 4(1H)-Pyrimidi, 2, 3-dihydro-6-propyl-2-thioxo-; 6-Propyl-2-Thiouracil; Accounting; Adult; Adverse Experience; Adverse event; Advisory Committees; Affect; American; Antithyroid Agents; Antithyroid Drugs; Asia; Basedow`s Disease; Birth Defects; Bone structure of cranium; California; Cardiac Abnormalities; Cardiac Defects, Congenital; Cardiac Malformation; Cardiac defect; Case Study; Cessation of life; Child; Child Youth; Children (0-21); Choanal Atresia; Clinical; Clinical Endocrinology; Clinical Research; Clinical Study; Cohort Studies; Complement; Complement Proteins; Concurrent Studies; Congenital Abnormality; Congenital Anatomic Abnormality; Congenital Anatomical Abnormality; Congenital Defects; Congenital Deformity; Congenital Heart Defects; Congenital Malformation; Congenital omphalocele; Corium; Cranium; Cutis; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Death; Dermis; Developmental Biology; Doctor of Medicine; Dose; Drug Therapy; Drug usage; Drugs; Early Placental Phase; Embryo; Embryo Development; Embryogenesis; Embryonic; Embryonic Development; Endocrine; Endocrinologist; Endocrinology; Epidemiology; Europe; European; FDA; Female of child bearing age; Female of childbearing age; Fetal Viability; Fetus; First Pregnancy Trimester; Food and Drug Administration; Food and Drug Administration (U.S.); Generalized Growth; Gestation; Goals; Goiter, Exophthalmic; Graves` Disease; Growth; Head and Neck, Thyroid; Heart Abnormalities; Heart Defects, Congenital; Heart Malformation; Hepatic Disorder; Hepatic Failure; Hepatotoxic effect; Hepatotoxicity; Human; Human, Adult; Human, Child; Human, General; Hyperthyroidism; IT Systems; Incidence; Individual; Infant; Information Systems; Information Technology Systems; Injury; Injury to Liver; International; Iodides; L-3, 5, 3`, 5`-Tetraiodothyronine; L-Thyroxine; Laboratories; Letters; Levothyroxine; Liver; Liver Failure; Liver Toxicity; Liver diseases; M.D.; Mammals, Mice; Man (Taxonomy); Man, Modern; Medication; Mercasolyl; Mercazolyl; Merkazolil; Metabolism and Endocrinology; Methimazole; Methods; Methylmercaptoimidazole; Mice; Modeling; Molecular Genetic Abnormality; Morphology; Mothers; Murine; Mus; Nature; O-(4-Hydroxy-3, 5-diiodophenyl) 3, 5-diiodo-L-tyrosine; O-(4-Hydroxy-3, 5-diiodophenyl)-3, 5-diiodotyrosine; Oceania; Omphaloceles; Operation; Operative Procedures; Operative Surgical Procedures; Perception; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Pregnancy; Pregnancy Trimester, First; Pregnant Women; Prevalence; Propylthiouracil; Radioactive Iodine; Recommendation; Relative Risks; Reporting; Research; Risk; Rivers; Skull; Societies; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Systems, Data; T4 Thyroid Hormone; Tapazole; Task Forces; Teratology; Testing; Therapeutic Levothyroxine; Thiamazole; Thyroid; Thyroid Antagonists; Thyroid Diseases; Thyroid Gland; Thyroid Gland Disease; Thyroid Gland Disorder; Thyroxine; Tissue Growth; Toxic effect on liver cells; Trimester, First; Tyrosine, O-(4-hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-; USFDA; United States; United States Food and Drug Administration; Universities; Woman; adult human (21+); adult youth; base; body system, hepatic; case report; children; clinical data repository; clinical data warehouse; congenital cardiac disorder; congenital heart disease; congenital heart disorder; cranium; data exchange; data repository; drug abuse in pregnancy; drug use; drug use in pregnancy; drug/agent; drugs used while pregant; epidemiology study; fetal drug exposure; gestational drug exposure; heart defect; hepatopathy; hepatoxicity; insight; liver disorder; malformation; member; offspring; ontogeny; organ system, hepatic; overactive thyroid; pregnant; pregnant drug abuser; prenatal drug exposure; prenatal drug use; prenatally drug exposed; public health relevance; relational database; surgery; thyroid disorder; thyroid inhibitor; thyroxin; women of child bearing age; women of childbearing age; young adult; youngster
Relevance: NARRATIVE The goal of these studies is to determine the risks of antithyroid drug therapy during pregnancy on mother and fetus. When completed, we anticipate that these studies will provide needed epidemiology and basic-teratology data about the relative risks of PTU, MMI, and hyperthyroidism to mother and fetus
Project start date: 2010-09-20
Project end date: 2014-05-31
Budget start date: 20-SEP-2010
Budget end date: 31-MAY-2011
PFA/PA: PA-07-070
1R01HD065200-01A1 (2010): $728127
A1-ADENOSINE RECEPTOR ACTION IN HIPPOCAMPUS
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R01NS033539-08 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: From s ) In contrast to classical neurotransmitters that are discretely released at synapses, adenosine is produced and released by all cells and diffuses into interstitial fluid. Adenosine exerts potent biological effects by activating specific receptors. The receptors include A1 adenosine receptors (A1ARs), which couple with Gi and Go and inhibit cAMP accumulation within cells. In the mammalian brain, A1ARs are widely expressed, with highest concentration found in the hippocampus. We have discovered that a unique feature of A1Ars is their high expression on axons. We have also found that A1ARs are expressed in the brain during critical periods of development. We also find that A1Ar activation in the neonatal period leads to significant reductions in total axon volume, indicating that A1AR impairs axon formation. Showing that adenosine can act directly on neurons to inhibit axon growth, A1AR agonists slow axonal growth in cultured hippocampal neurons. Although it is recognized that G proteins are heavily expressed on axons, the receptor systems that regulate axonal G proteins are largely unknown. We hypothesize that adenosine is an important regulator of axonal G proteins and that activation of axonal A1ARs during development inhibits axon growth. We also hypothesize that activation of A1ARs during the neonatal period may impair brain development. This application presents a focused series of studies aimed at testing this hypothesis and elucidating the mechanisms of neuronal A1AR action. To test our hypothesis (1) we will examine the effects of adenosine on axon formation in vivo. (2) We will examine the effects of A1Ar activation on axon growth in cultured hippocampal neurons. (3) We will elucidate the mechanisms by which A1AR activation inhibits axon growth. We anticipate these studies will lead to new insights into the mechanisms of A1AR action. We also anticipate that these studies will identify A1ARs as an important regulator of axon growth.
Keywords: G protein, adenosine, developmental neurobiology, hippocampus, neurogenesis, protein structure function, purinergic receptor, receptor expression, adenosine deaminase, axon, cyclic AMP, developmental genetics, neurotransmitter metabolism, neurotransmitter transport, protein kinase A, receptor binding, immunocytochemistry, laboratory mouse, site directed mutagenesis, tissue /cell culture
Project start date: 1996-05-01
Project end date: 2005-06-30
5R01NS033539-08 (2003): $327000
Sponsored Links Excellgen http://Excellgen.com
5R01NS033539-07 (2002): $327000
5R01NS033539-06 (2001): $327000
2R01NS033539-05A2 (2000): $327000
PERIVENTRICULAR WHITE MATTER INJURY PREVENTION
Scott A Rivkees, Associate Chair Of Pediatrics
Yale University, 47 College Street, Ste 203, New Haven, Ct 06520-8047
Grant 1R01NS068039-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: Five to twenty percent of low birth weight preterm infants manifest some form of periventricular white matter injury (PWMI), making it the most common form of brain injury affecting premature infants 1-2. PWMI includes a spectrum of brain injury ranging from diffuse white matter disease to focal necrosis 2-4. PWMI is associated with significant morbidity, as affected individuals may have profound intellectual impairment and cerebral palsy 5-7. Highlighting the magnitude of PWMI, each year in the United States more than 400,000 infants are born prematurely 8. Of these infants, 150,000 are born at risk for PWMI, and about 25,000 children per year will develop PWMI. World-wide, 1,000,000 infants will be born each year at risk for PWMI, and about 250,000 children per year will develop PWMI. It is estimated the lifetime care costs for infants who develop cerebral palsy due to PWMI exceeds $1.5 million per infant9. Thus, finding a prevention and treatment for PWMI is of major public health importance. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation 10-13. It is believed that due to loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation 3. Presently, we are unaware of pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. Recently, we used high-throughput screening to identify compounds ("hits") that would stimulate PreOL proliferation. These studies proved to be highly successful. We identified diazoxide as a stimulator of PreOL proliferation and showed that this compound promotes myelination in a murine model of PWMI. Diazoxide acts by activating KATP channels 14-15. We also found that other KATP activators stimulate PreOL proliferation. We also identified KATP channel component in OLs. We thus hypothesize that diazoxide will be a potential novel therapeutic for PWMI, and that we have discovered a novel therapy for PWMI. We propose to extend our study of diazoxide in preclinical, proof-of-concept studies involving cell culture and animal studies. These studies have been developed with direction form the US Food and Drug Administration and experts in central nervous system (CNS) medicinal chemistry. More specifically we will 1. Assess diazoxide neonatal toxicity. 2. Define OL-stage specific responses to diazoxide. 3. Evaluate protection against PWMI in animal models. 4. Assess long-term effects of neonatal diazoxide therapy. 5. Identify alternative diazoxide-derivative compounds These studies will focus on the lead compound diazoxide for several reasons. First, diazoxide is a generic drug that is approved by the US Food and Drug Administration (FDA) for the acute treatment of hypertension and the treatment of hyperinsulinism in infants15-16. Second, diazoxide is currently the treatment of choice for infants with hyperinsulinism, and major adverse events related to diazoxide use in infants have not been reported 17. Third, there is favorable clinical and commercial precedent for developing new use indications for generic drugs18-20. Fourth, toxicology studies show that diazoxide has a very broad therapeutic index, with an LD50 value greater than 500 mg/kg in neonatal rodents. This value compares very favorably with the effective 10 mg/kg dose used in our studies. As such, we will avoid the high costs and the lengthy time frame associated with new drug development in applying FDA-approved, generic drugs for novel clinical applications. The long-term goal of this work is to develop novel therapeutic agent for the treatment of PWMI in premature infants. Ultimately, research such as this will lead to important discoveries with significant public health benefit for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year. The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year
Relevance: NARRATIVE The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year
Project start date: 2010-05-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PAR-10-001
1R01NS068039-01A1 (2010): $362031
Anti-Adenosine Therapy Of Neonatal Brain Injury
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R21NS051191-02 from National Institute Of Neurological Disorders And Stroke IRG: NSD
Abstract: Five to ten percent of premature infants will sustain significant neurological injuries. Periventricular white matter injury (PWMI) is now the most common cause of brain injury in preterm infants and is characterized by a loss of white matter and secondary ventricular enlargement. Unfortunately, strategies aimed at directly preventing PWMI are not available. Recently we discovered that adenosine, acting through A1 adenosine receptors (A1ARs), plays a major role in the pathogenesis of PWMI. We find that hypoxic rearing is associated with abnormal maturation of oligodendrocytes and delayed myelination, as in PWMI. Importantly, blockade of A1 ARs prevents hypoxia-induced ventriculomegaly and reduced myelination. Based on these observations we believe that it is possible to prevent hypoxia-induced brain injury and PWMI by blocking adenosine action using drug therapy. To develop a new clinical strategy for PWMI prevention, we propose the following Specific Aims SA1. Test four different approaches for blocking adenosine action in hypoxia, including PEG-adenosine deaminase, which degrades adenosine and is an FDA approved drug; caffeine, which is a non-specific adenosine antagonist and is an FDA approved drug; 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), which is a potent and highly selective A1AR antagonist; SCH58261, which is an A2aAR antagonist. SA2. Test the effectiveness of the above approaches in preventing hypoxia-induced brain injury. SA3. Test the effectiveness of anti-adenosine therapy in preventing hypoxia-induced behavior disturbances. It is anticipated that these studies will lead to novel and practical strategies for directly preventing brain injury.
Keywords: adenosine, brain injury, hypoxia, therapy, Primate, adenosine deaminase, aminohydrolase, anatomy, base, behavior, brain, caffeine, cell, cerebral hemorrhage, cerebral palsy, chemotherapy, children, hemorrhage, human, inflammation, injury, ischemia, lead, learning disorder, mental retardation, myelin, myelination, oligodendroglia, play, prevention, purinergic receptor, reduction, role, tissue, white matter
Project start date: 2006-01-01
Project end date: 2008-12-31
5R21NS051191-02 (2007): $170280
1R21NS051191-01A1 (2006): $183938
Vaccine Therapy Of Congenital Adrenal Hyperplasia
Scott A Rivkees, Professor
L2 Diagnostics, Llc New Haven, Ct 06530
Grant 1R41DK064528-01 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZRG1
Abstract: Congenital virilizing adrenal hyperplasia (CAH) is caused by impaired adrenal steroidogenesis that results in reduced production of cortisol and aldosterone, and excessive production of androgens. Whereas there are consequences of reduced cortisol and aldosterone production, increased androgen is responsible for most of the adverse effects of this condition. In normal conditions and in CAH, excessive androgen production is regulated by pituitary ACTH, which acts via the melanocortin-2 receptor (MC2R) in the adrenal gland to stimulate steroid production. If activation of the MC2R can be inhibited, adrenal activity in CAH will be markedly reduced and management optimized. In this application we propose the development of a novel immunological approach for inducing adrenal insufficiency in patients with CAH by making a vaccine that inhibits ACTH-mediated activation of the MC2R. This application is based on preliminary studies showing that antibodies to the MC2R inhibit the ability of ACTH to activate MC2R function in adrenal cells. We also find that immunizing mice with synthetic peptides that correspond to small regions of the MC2R induces an immune response against the MC2R. Based on these observations, we hypothesize that it is possible to develop a "vaccine" against the MC2R that blocks ACTH action. We also hypothesize that a vaccine against the MC2R will lead to improved treatment of CAH, To test these hypotheses we propose to (1) induce immunity against the MC2R by immunizing mice with modified peptides. (2) Determine if vaccinating mice with modified MC2R peptides leads to adrenal insufficiency. We anticipate that these studies will lead to the development of a novel approach for treating patients with CAH. If these phase I studies are effective, phase II studies will focus on preclinical trials in non-human primates. We also anticipate being able to extend this novel approach to the treatment of other receptor-mediated endocrine disorders, such as hyperthyroidism.
Keywords: adrenocorticotropic hormone, congenital adrenal hyperplasia, endocrine pharmacology, hormone receptor, vaccine development, vector vaccine, active immunization, adrenal gland, drug screening /evaluation, hypoadrenalism, peptide, vaccine evaluation, biotechnology, laboratory mouse
Project start date: 2003-09-01
Project end date: 2004-08-31
1R41DK064528-01 (2003): $135039
ADENOSINERGIC MECHANISMS OF INTRAUTERINE GROWTH RETARDATION
Scott A Rivkees
Yale University, 47 College Street, Ste 203, New Haven, Ct 06520-8047
Grant 5R01HD058086-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Compelling evidence suggests that alteration of normal prenatal development influences one´s lifetime risks for obesity and cardiovascular disorders, which are components of the metabolic syndrome. Reflecting the public health importance of elucidating risk factors for obesity and cardiovascular disease, the metabolic syndrome affects nearly 50 million Americans. Thus, efforts aimed at elucidating the risk factors for adult disease, including those that contribute to a small element of causation, are of major public health and economic importance. The goals of this proposal are to identify the mechanisms by which adenosine acts to protect the embryo in utero and how altered embryonic adenosine action leads to long-term adverse effects in adulthood
Keywords: 1, 3, 7-Trimethylxanthine; 1H-Purine-2, 6-dione, 3, 7-dihydro-1, 3, 7-trimethyl-; 21+ years old; Acute; Adenosine; Adenosine A1 Receptor; Adult; Adverse effects; Affect; Air Pollution; American; Body Composition; Body Tissues; Body fat; Caffeine; Cardiac; Cardiac Abnormalities; Cardiac Defects, Congenital; Cardiac Malformation; Cardiac defect; Cardiovascular Diseases; Causality; Cell Communication and Signaling; Cell Signaling; Coffee; Congenital Heart Defects; Consumption; Development; Diabetes Mellitus; Disease; Disorder; Dose; Dysfunction; Effects, Longterm; Elements; Embryo; Embryo Development; Embryogenesis; Embryonic; Embryonic Development; Environmental Factor; Environmental Risk Factor; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Etiology; Fetal Development; Fetal Growth Restriction; Fetal Growth Retardation; Fetal development of the mammalian embryo or fetus; Foundations; Functional disorder; Gene Expression; Generalized Growth; Genetic Alteration; Genetic Change; Genetic defect; Genomics; Gestation; Goals; Growth; HIF 1; HIF-1 protein; HIF1; HIF1 protein; Heart; Heart Abnormalities; Heart Defects, Congenital; Heart Malformation; Human, Adult; Hypoxia; Hypoxic; IUGR; Infant; Intracellular Communication and Signaling; Intrauterine Growth Retardation; Lifetime Risk; Long-Term Effects; Mammals, Mice; Mediating; Metabolic; Metabolic syndrome; Mice; Modification; Murine; Mus; Mutation; Nutrient; O element; O2 element; Obesity; Organogenesis; Oxygen; Oxygen Deficiency; Pattern; Physiology; Physiopathology; Play; Population; Predisposition; Pregnancy; Pregnant Women; Proteins; Public Health; Risk Factors; Role; Signal Transduction; Signal Transduction Systems; Signaling; Site; Smoking; Susceptibility; Testing; Tissue Growth; Tissues; Transgenic Mice; Treatment Side Effects; Ventricular; Woman; ing; adiposity; adult human (21+); adult youth; base; biological signal transduction; cardiogenesis; cardiovascular disorder; corpulence; corpulency; corpulentia; cost; diabetes; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; environmental risk; fetal programming; gene product; genome mutation; health economics; heart defect; heart development; high risk; hypoxia inducible factor 1; in utero; insight; intrauterine growth restriction; new approaches; novel approaches; novel strategies; novel strategy; obese; obese people; obese person; obese population; offspring; ontogeny; pathophysiology; prenatal; prenatal growth disorder; prevent; preventing; protective effect; protein expression; public health medicine (field); side effect; social role; stressor; therapy adverse effect; treatment adverse effect; unborn; young adult
Relevance: NARRATIVE These studies are directed at identifying how adenosine acts via A1ARs and HIF1-¿ to confer embryo protection and if altered embryonic adenosine signaling leads to fetal programming of adult disease
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PA-07-070
5R01HD058086-02 (2010): $410198
1R01HD058086-01A2 (2009): $413750
DEVELOPING CIRCADIAN RHYTHMICITY
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R01NS032624-09 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: applicant s ) Although 250,000 preterm infants are reared in artificial environments of hospital nurseries in the United States each year, very little consideration is given to the lighting cycles to which infants are exposed. In neonatal intensive care units, preterm infants are typically exposed to continuous dim lighting without photic time-of-day cues. In the absence of photic entraining signals, the oscillations of the developing circadian clock will drift out of synchrony with the circadian phase of the mother and the external light-dark cycle. This desynchrony may compromise maternal-child interactions, resulting in increased infant irritability and increased newborn energy expenditure. To extend principals of circadian biology to the care of human newborns, fundamental issues, such as when the developing primate clock becomes responsive to light, need to be addressed. Thus, several years ago we initiated a series of basic studies aimed at characterizing primate circadian system development. Using baboons to model human circadian system development, we discovered that the circadian pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) is functionally innervated by the retina in very premature infants. We have also discovered that low-intensity lighting (200 lux) entrains developing primate rhythmicity. Based on the above observations, we hypothesize that (1) human infants are entrained by low-intensity cycled lighting at very immature stages, (2) entrainment of the developing circadian clock leads to the earlier establishment of rest-activity cycles, and (3) neonatal entrainment improves parent-infant interactions and neonatal growth. To test these hypotheses, first we will examine influences of lighting cycles on the development of rest-activity patterns. Second, we will examine influences of cycled lighting on growth and energy expenditure. Third, we will examine the influence of cycled lighting on neonatal behavior and parent-infant interactions. These studies will involve a multidisciplinary approach combining expertise in neonatalogy, circadian biology, and child development at a single institution. Each specific aim will involve inpatient investigations, where controlling the environmental conditions is possible. We have also designed outpatient studies to test if photic entrainment before discharge is associated with long-term beneficial influences on activity, growth, infant behavior, and maternal-child interactions. In comparison with the considerable number of research initiatives aimed at examining the role of the circadian system and environmental lighting influences on human adults, circadian system-related studies of children are scant. Thus, our proposal will address recent initiatives for encouraging more child-related investigational research. We anticipate that these studies will improve new insights into the role of the circadian system and environmental lighting on the developing human infant. These studies may also lead to the development of new care practices in Neonatal Intensive Care Units and extend the field of developmental chronobiology to the bedside.
Keywords: circadian rhythm, growth /development, parent offspring interaction, photobiology, premature infant human, lighting, personality, behavioral /social science research tag, clinical research, human subject
Project start date: 1994-12-01
Project end date: 2004-06-30
5R01NS032624-09 (2002): $372322
Sponsored Links Excellgen http://Excellgen.com
5R01NS032624-08 (2001): $375375
5R01NS032624-07 (2000): $354816
HUMAN A1 ADENOSINE RECEPTOR ACTION IN HIPPOCAMPUS
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R01NS033539-04 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: Adenosine is a nucleoside that influences the activity of numerous tissues by binding to specific cell surface receptors. Growing evidence suggests that A1 adenosine receptors (A1ARs) are important neuromodulators that are widely distributed in the mammalian brain. A1ARs are believed to tonically inhibit neural activity, and activation of A1ARs can stop seizures. A1ARs may modulate the action of excitatory neurotransmitters, and A1AR activation also may help protect the brain against injury. Increasing evidence suggests that the hippocampal formation is an important site of A1AR action. In comparison with what is known about other receptor systems in the brain, surprisingly little is known about the neural adenosinergic system. Using contemporary molecular and biochemical techniques, we propose to examine the sites and mechanisms of A1AR action in the hippocampus. First, we will identify the cellular sites of A1ARs in human hippocampus. We will use immunohistochemistry, receptor autoradiography and in situ hybridization for these studies. Second, we will examine the structural basis of how the human A1AR interacts with agonists and antagonist. Using chimeric receptors, we will identify transmembrane domains of that are important for ligand binding. We will then use small chimeric constructs and site-directed mutagenesis to localize specific amino acids that are important for binding agonists, antagonists, and adenosine enhancers. Third, we will examine if A1AR activation alone influences hippocampal physiology, and examine if adenosine itself acts predominantly via A1ARs. Using rat hippocampal slices, we will examine if A1ARs inhibit excitatory amino acid release and examine if A1ARs influence hippocampal gene expression. A1ARs may play a very important role in the pathogenesis and treatment of nervous system disorders including epilepsy. Understanding the basic mechanisms of human A1AR action in hippocampus, will allow us to better understand the role of this important receptor system in human neural physiology.
Keywords: protein structure /function, purinergic receptor, receptor expression, adenosine, excitatory aminoacid, gene induction /repression, glutamate, inhibitor /antagonist, neural inhibition, neurotransmitter transport, receptor binding, stimulant /agonist, autoradiography, hippocampus, immunocytochemistry, in situ hybridization, laboratory rat, site directed mutagenesis
Project start date: 1996-05-01
Project end date: 2000-03-31
5R01NS033539-04 (1998): $238110
5R01NS033539-03 (1997): $236166
ADENOSINE ACTION IN THE DEVELOPING HEART
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 1R01HL058442-01 from National Heart, Lung, And Blood Institute IRG: HED
Abstract: Adapted from s ) The proposed studies are designed to test the hypothesis that A1 adenosine receptors (A1ARs) activate functional effector systems in embryonic hearts to regulate cardiac activity. Further, it is proposed that A1AR activation during critical periods of heart formation affects cardiac structural development. Four specific aims are proposed. 1) The effector systems through which A1ARs influence fetal cardiac physiology will be defined. 2) A determination will be made whether A1AR activation influences cardiac structural development. 3) Transgenic mice will be generated by fusing the wild-type A1AR receptor with the atrial natriuretic factor promoter. 4) The A1AR promoter will be characterized and transgenic animals expressing high affinity A1ARs will be generated.
Keywords: adenosine, embryogenesis, mammalian embryology, myocardium, neurotransmitter receptor, atrial natriuretic peptide, fusion gene, genetic promoter element, heart function, nucleic acid sequence, receptor expression, animal genetic material tag, embryo /fetus culture, laboratory mouse, organ culture, transgenic animal
Project start date: 1997-08-15
Project end date: 2001-07-31
1R01HL058442-01 (1997): $257934
5R01HL058442-04 (2000): $270552
5R01HL058442-02 (1998): $259648
The Role Of Adenosine In Hypoglycemic Brain Injury
Scott A Rivkees, Professor
Yale University 47 College Street, Ste 203 New Haven, Ct 065208047
Grant 5R21NS045310-02 from National Institute Of Neurological Disorders And Stroke IRG: ZNS1
Abstract: Acute episodes of hypoglycemia are associated with long-term neurological injury, and it has been suggested that the developing brain may be more sensitive to the adverse affects of hypoglycemia. Potential mediators of hypoglycemia in the brain include adenosine. However, our understanding of the role that adenosine plays in hypoglycemia-induced brain injury is limited, as is our understanding of the developmental susceptibility of the brain to hypoglycemic damage. We have recently found that acute hypoglycemia (1.5 mM; 27 mg/dl; 6-12 hrs) results in much more neuronal death in younger than in older animals. In addition, we find that blockade of A1 adenosine receptor (A1AR) action reduces hypoglycemia-induced neuronal death. We also find that hypoglycemia leads to both neuronal and oligodendrocyte injury, possibly due to perturbations in intracellular Ca2+ signaling. Based on these observations, we hypothesize (a) that the developing brain is especially sensitive to the adverse effects of low glucose levels, (b) hypoglycemia leads to increased AIAR action, resulting in neuronal and oligodendrocyte injury, and (c) A1AR antagonists will reduce hypoglycemic brain injury. To test these hypotheses, (1) we will examine the developmental susceptibility of the brain to hypoglycemic injury. (2) We will assess the roles of A1ARs in mediating hypoglycemic injury. (3) We will examine mechanisms of hypoglycemic injury in neurons, and (4) oligodendrocytes. In many previous studies of hypoglycemia, non-physiological paradigms have been used that include the combination of hypoxia and hypoglycemia, aglycemia, or extended hypoglycemia. Thus, to provide insights into the effects of hypoglycemia, we will examine responses to glucose levels associated with clinical hypoglycemia (0.75-3 mM), without hypoxia or other metabolic insults. We will also focus on short-term, low glucose exposure. We anticipate that these studies will yield new insights into the mechanisms of hypoglycemic brain injury and may lead to the development of practical strategies for reducing hypoglycemic brain injury.
Keywords: adenosine, developmental neurobiology, hypoglycemia, nerve injury, glucose metabolism, inhibitor /antagonist, oligodendroglia, purinergic receptor, laboratory mouse, laboratory rat, tissue /cell culture, transgenic animal
Project start date: 2002-09-30
Project end date: 2005-07-31
5R21NS045310-02 (2003): $204375
DIFFUSION WEIGHTED IMAGING BY 3D GPSW SPIN ECHO SEQUENCE TO ACQUIRE 12 IMAGES EN
Scott A Rivkees, Professor
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5P41RR005959-150134 from National Center For Research Resources IRG: ZRG1
Keywords: biomedical resource, image enhancement, imaging /visualization /scanning, method development, three dimensional imaging /topography, bioimaging /biomedical imaging
Project start date: 2004-07-01
Project end date: 2005-06-30
DEVELOPING CIRCADIAN RHYTHMICITY
Scott A Rivkees, Professor
Indiana Univ-purdue Univ At Indianapolis 620 Union Drive, Room 618 Indianapolis, In 462025167
Grant 5R01NS032624-02 from National Institute Of Neurological Disorders And Stroke IRG: NEUB
Project start date: 1994-12-01
Project end date: 1996-09-30
5R01NS032624-02 (1996): $269579
Sponsored Links Excellgen http://Excellgen.com
HUMAN A1 ADENOSINE RECEPTOR ACTION IN HIPPOCAMPUS
Scott A Rivkees, Professor
Indiana Univ-purdue Univ At Indianapolis 620 Union Drive, Room 618 Indianapolis, In 462025167
Grant 1R01NS033539-01A2 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Project start date: 1996-05-01
Project end date: 1996-09-30
1R01NS033539-01A2 (1996): $208346