PHYSIOLOGY OF THYROID HORMONE-DEPENDENT GENE EXPRESSION
Philip Reed Larsen, Professor
Brigham And Women´s Hospital, Research Administration, Boston, Ma 02115
Grant 5R01DK044128-18 from National Institute Of Diabetes And Digestive And Kidney Diseases
Keywords: 2-Naphthacenecarboxamide, 4-(dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 5, 10, 12, 12a-pentahydroxy-6-methyl-1, 11-dioxo-, (4S-(4alpha, 4aalpha, 5alpha, 5aalpha, 6alpha, 12aalpha))-; 3, 5, 3`, 5`-Tetraiodothyronine; 5`-Deiodinase; Animals; Autoregulation; BCC; Basal cell carcinoma; Basiloma; Binding Sites; Biological Models; Bone; Bone and Bones; Bones and Bone Tissue; Cancers; Carcinoma Cell; Carcinoma, Basal Cell, Pigmented; Cells; Chronology; Collaborations; Combining Site; Data; Deiodinase; Deiodinase, Iodothyronine; Development; Doxycycline; E3 Ligase; E3 Ubiquitin Ligase; EC 1.11.1.8; Energy Expenditure; Energy Metabolism; Enzymes; Epithelial Cells; Epithelioma, Basal Cell; Erinaceidae; Event; Fibroblasts; GFAC; Gene Expression; Genes; Genetics, in situ Hybridization; Grant; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Hair Follicle; Hair follicle structure; Head and Neck, Thyroid; Health; Hedgehogs; Homeostasis; Human; Human, General; In Situ Hybridization; Investigation; Investigators; Iodide Peroxidase; Iodide[{..}]hydrogen-peroxide oxidoreductase; Iodinase; Iodoperoxidase (Heme Type); Iodothyronine Deiodinase; Iodotyrosine Deiodase; Iodotyrosine Deiodinase; Knowledge; L-3, 5, 3`, 5`-Tetraiodothyronine; L-Thyroxine; L-Triiodothyronine; L-Tyrosine, O-(4-hydroxy-3-iodophenyl)-3, 5-diiodo-; Levothyroxine; Liothyronine; Malignant Epithelial Cell; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Metabolic; Metabolic Pathway; Methods and Techniques; Methods, Other; Mice; Mice, Transgenic; Model System; Modeling; Models, Biologic; Monodeiodinase; Monoiodotyrosine Deiodinase; Morphogenesis; Murine; Mus; Muscle; Muscle Cells; Muscle Cells, Mature; Muscle Fibers; Muscle Tissue; Muscle, Skeletal; Muscle, Voluntary; Myocytes; Myotubes; O-(4-Hydroxy-3, 5-diiodophenyl) 3, 5-diiodo-L-tyrosine; O-(4-Hydroxy-3, 5-diiodophenyl)-3, 5-diiodotyrosine; Obesity; Oncogenesis; Organ; Pathway interactions; Physiologic; Physiological; Physiological Homeostasis; Physiology; Play; Process; Programs (PT); Programs [Publication Type]; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Proteins; Publishing; Reactive Site; Receptors, Thyroid Stimulating Hormone; Recombinant TSH; Recombinant Thyroid-Stimulating Hormone; Regulation; Research Design; Research Personnel; Researchers; Rhabdomyocyte; Role; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal Muscle Tissue; Skeletal Myocytes; Skeletal muscle structure; Skin; Skin Basal Cell Carcinoma; Study Type; System; System, LOINC Axis 4; T-3; T3 Thyroid Hormone; T4 Thyroid Hormone; TSH Receptors; Techniques; Testing; Tet; Tetanus Helper Peptide; Therapeutic Levothyroxine; Therapeutic T3; Therapeutic Triiodothyronine; Thyreotropin; Thyroid; Thyroid Gland; Thyroid Gland Hormone; Thyroid Hormones; Thyroid Peroxidase; Thyroid Stimulating Hormone; Thyroid-Stimulating Hormone; Thyroperoxidase; Thyrotoxicosis; Thyrotropin; Thyrotropin Receptor; Thyroxine; Transgenic Mice; Triiodothyronine; Tyrosine Iodinase; Tyrosine, O-(4-hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-; Ubiquitin-Protein Ligase E3; Ulcer, Rodent; Vibramycin; Wound Healing; Wound Repair; adiposity; alpha-6-Deoxyoxytetracycline; bone; corpulence; corpulency; corpulentia; fetal; gene product; in situ Hybridization Staining Method; keratinocyte; malignancy; muscle metabolism; neoplasm/cancer; novel; obese; obese people; obese person; obese population; pathway; programs; social role; study design; thyroxin; tissue repair; tumorigenesis; ubiquitin-protein ligase
Project start date: 1992-01-15
Project end date: 2010-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
5R01DK044128-18 (2010): $336053
Sponsored Links Excellgen http://Excellgen.com
PHYSIOLOGY OF THYROID HORMONE-DEPENDENT GENE EXPRESSION
Philip Reed Larsen, Professor
Brigham And Women´s Hospital
Grant 5R01DK044128-17 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: MCE
Project start date: 1992-01-15
Project end date: 2010-12-31
Grants awarded to Philip Reed Larsen
TRAINING GRANT IN ACADEMIC ENDOCRINOLOGY
Philip Reed Larsen, Professor
Brigham And Women´s Hospital, Research Administration, Boston, Ma 02115
Grant 5T32DK007529-24 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This is a 5-year renewal application to support five postdoctoral trainees for a broad program in Academic Endocrinology. This program is now in its 27th year, and its faculty has had a highly successful record of training physicians and Ph.D.s for careers in academic medicine. The Training Faculty includes both physician scientists at the Brigham and Women´s Hospital and basic scientists with endocrinologically relevant research programs who have primary appointments at Harvard Medical School. They are well funded with over $10 million in direct NIH research awards annually excluding the General Clinical Research Center Grant. The Program Goal is to train individuals who will provide new insights into the pathophysiology of endocrine-related diseases and the mechanisms of hormone action on various physiological processes. The five trainees appointed each year will be individuals with M.D., Ph.D., or M.D./Ph.D. degrees, and training will consist of 3-4 years of intensive research experience in either basic or clinical investigation. Trainees are expected to acquire sufficient expertise to apply successfully for independent entry-level NIH support and to initiate a successful career in biomedical sciences in a Medical or Basic Science Department. The major research areas include thyroid hormone activation and inactivation and especially its roles in energy expenditure and central nervous system and bone development; calcium receptor structure, function and pathophysiology; studies of aldosterone cardiotoxicity and the role of the renin angiotensin system in cardiac failure; the neuroendocrinology of reproduction and estrogen action; the pathophysiology of skeletal homeostasis; causes and treatment of osteoporosis; diagnosis and treatment of acquired and inherited causes of hypertension; sleep disorders; the biology and pathophysiology of protein turnover; and the genetic regulation of energy utilization. The individuals trained under this proposal will spend their research careers applying the insights they gain to develop strategies for the treatment and eventually the prevention of significant public health problems including diabetes mellitus, obesity, osteoporosis, hypertension and congestive heart failure as well as hormone-dependent tumors such as breast and prostate cancer
Keywords: Endocrinology; Grant; Metabolism and Endocrinology; Training
Project start date: 1985-07-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-02-109
5T32DK007529-24 (2010): $149956
5T32DK007529-23 (2009): $133241
5T32DK007529-22 (2008): $184013
PHYSIOLOGICAL ROLE OF THYROXINE-BINDING PROTEINS
Philip Reed Larsen
Department/ Educational Institution Type:
Grant 5R03TW007559-03 from Fogarty International Center
Abstract: This collaborative study will be performed in Brazil at the Endocrinology Division, Medical School of the Universidade Federal do Rio Grande do Sul, as an extension of NIH grant # RO1 DK-36256 to extend studies on the function of the iodothyronine deiodinases under physiological and pathophysiological circumstances in humans. The types 1, 2, and 3 deiodinases (D1,D2, and D3) constitute a family of oxidoreductases that catalyze the removal of iodine from the outer (D1 and D2, activation) or inner ring (D1 and D3, inactivation) of the thyroid hormones. The deiodination pathway is a critical step in thyroid hormone activation and inactivation, allowing for rapid changes in intracellular thyroid status in a tissue-specific manner, without affecting systemic thyroid hormone levels. In these studies, we will explore the mechanism of catalysis in intact cells by the third member of the selenodeiodinase family, D3. The D3 enzyme catalyzes the inactivation of T4 and T3 and its overexpression, as occurs in large hemangiomas, causes severe hypothyroidism in infants and adults. Increases in D3 activity, causing local hypothyroidism, may also be important in the adaptive response of humans to illness or fasting to conserve energy. Furthermore, increased D3 activity has been demonstrated in failing hearts, indicating that reduction of local intracellularTS may contribute to a hypothyroid condition in the myocardium. Our confocal microscopic studies predict that the active catalytic center of D3 is extracellular. We will determine if thyroid hormone inactivation by D3 occurs in the extracellular space and whether catalysis can be altered by either covalent modification of the enzyme by impermeant probes or by blocking the normal intracellular cycling of D3. The studies proposed here will shed light on the function of this deiodinase and will have major implications for our understanding of factors controlling thyroid hormone levels in healthy and sick individuals
Keywords: 21+ years old; 3, 5, 3`, 5`-Tetraiodothyronine; 3-iodothyronine; 3-monoiodothyronine; 3-T1; 5`-Deiodinase; Abscission; Address; Adult; adult human (21+); Affect; Amino Acids; aminoacid; Angioma; Benign Angioma; Benign Hemangioma; Binding; Binding (Molecular Function); Biochemical; Biological; Blood Circulation; Blood Plasma; Bloodstream; body system, hepatic; Body Tissues; Brazil; cardiac muscle; Catalysis; Cell Nucleus; Cells; Chemotherapy-Hormones/Steroids; Circulation; cofactor; Confocal Microscopy; Dehydrogenases; Deiodinase; deiodination; Development; EC 1.11.1.8; Endocrine Gland Secretion; Endocrinology; Enzymes; Excision; Extirpation; extracellular; Extracellular Space; Family; fasted; Fasting; fasts; Gene Expression; gene product; Grant; Head and Neck, Thyroid; Heart; heart muscle; Hemangioma; Homodimerization; Hormones; Human; Human, Adult; Human, General; hypothalamic; Hypothalamic structure; Hypothalamus; Hypothyroidism; I- element; In Vitro; in vitro Model; in vivo; Individual; Infant; Integral Membrane Protein; Intercellular Space; Intrinsic Membrane Protein; Investigation; Iodide Peroxidase; Iodide[{..}]hydrogen-peroxide oxidoreductase; Iodinase; Iodine; iodine deficiency; iodine deficiency syndrome; Iodoperoxidase (Heme Type); Iodothyronine Deiodinase; Iodotyrosine Deiodase; Iodotyrosine Deiodinase; Kidney; L-3, 5, 3`, 5`-Tetraiodothyronine; L-Thyroxine; Levothyroxine; Life; Light; Liver; Mammals, Rodents; Man (Taxonomy); Man, Modern; medical schools; member; Metabolism and Endocrinology; Methods and Techniques; Methods, Other; Microscopic; Modification; Molecular; Molecular Interaction; Monitor; Monodeiodinase; Monoiodotyrosine Deiodinase; Muscle, Cardiac; Muscle, Heart; Myocardium; National Institutes of Health; National Institutes of Health (U.S.); NIH; Nuclear; Nucleus; O-(4-Hydroxy-3, 5-diiodophenyl) 3, 5-diiodo-L-tyrosine; O-(4-Hydroxy-3, 5-diiodophenyl)-3, 5-diiodotyrosine; O-(4-hydroxyphenyl)-3-iodotyrosine; organ system, hepatic; overexpression; Oxidoreductase; parent grant; pathway; Pathway interactions; Pattern; Photoradiation; Physiologic; Physiological; Physiology; pituitary thyroid axis; Plasma; Principal Investigator; Production; programs; Programs (PT); Programs [Publication Type]; prohormone; Property; Property, LOINC Axis 2; Proteins; Recombinants; Reductases; Regulation; Relative; Relative (related person); Removal; renal; Repression; resection; response; Reticuloendothelial System, Serum, Plasma; Rodent; Rodentia; Rodentias; Role; Serum, Plasma; simulation; social role; Source; Surgical Removal; System; System, LOINC Axis 4; T4 Thyroid Hormone; Techniques; Therapeutic Hormone; Therapeutic Levothyroxine; Thyroid; Thyroid Gland; Thyroid Gland Hormone; Thyroid Hormones; Thyroid Peroxidase; Thyroperoxidase; thyroxin; Thyroxine; Thyroxine Transport Protein; Thyroxine-Binding Proteins; Time; Tissues; Transmembrane Protein; Tyrosine Iodinase; Tyrosine, O-(4-hydroxy-3, 5-diiodophenyl)-3, 5-diiodo-; United States National Institutes of Health; uptake; Urinary System, Kidney
Project start date: 2007-01-01
Project end date: 2010-12-31
Budget start date: 1-JAN-2009
Budget end date: 31-DEC-2010
PFA/PA: PAR-05-072
5R03TW007559-03 (2009): $39372
5R01DK036256-26 (2010): $369765