GENE THERAPY FOR SICKLE CELL DISEASE
Malik Punam, Associate Professor
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Keywords: Accounting; Affect; Allogenic; Anemia; Autologous; Azacitidine; beta Globin; beta Thalassemia; Bone Marrow; Butyrates; CD34 gene; Cells; chemotherapy; Chromatin; Clinic; Clinical; Clinical Research; Codon Nucleotides; Collection; conditioning; Decitabine; design; Elements; Engraftment; Equilibrium; Erythroid; Erythroid Cells; Erythropoiesis; Fanconi`s Anemia; Fetal Hemoglobin; gene therapy; gene therapy clinical study; Gene Transfer; Genes; Genetic; genetic manipulation; Globin; Goals; Harvest; Hematopoietic stem cells; Hemoglobin F Disease; Human; hybrid gene; hydroxyurea; improved; In Vitro; in vivo Model; Laboratories; Lentivirus Vector; Life; Malignant Neoplasms; Mediating; Modeling; Mus; Patients; Peripheral Blood Stem Cell; Pharmaceutical Preparations; Phase; Phenotype; pilot trial; polymerization; pre-clinical; preclinical study; prevent; Production; Protocols documentation; Recombinants; Reporting; RNA Interference; Safety; safety study; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; sickling; small hairpin RNA; Source; Stem cell transplant; Stem cells; Therapeutic; Time; Toxic effect; vector
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5U54HL070871-09_5690 (2011): $211963
Sponsored Links Excellgen http://Excellgen.com
A PHASE I/II TRIAL OF ZILEUTON IN SICKLE CELL DISEASE
Malik Punam, Associate Professor
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Abstract: Inflammation is increasingly recognized as a key feature of sickle cell disease, potentially linking vaso-occlusion, endothelial cell dysfunction, reactive airway disease and pulmonary hypertension. Acutely, inflammation is triggered by hypoxia-reperfusion injury resulting from vaso-occlusion; chronically, it is sustained by the abnormal cytokine milieu perpetuated by chronic hypoxia and by release of placenta growth factor, a strong proinflammatory molecule released from the stimulated erythron in sickle cell disease. We show that placenta growth factor increases leukotriene synthesis via upregulation of 5-lipoxygenase, which catalyzes production of leukotrienes. Leukotrienes are among the most potent proinflammatory molecules for polymorphonuclear cells, and increase airway hyperreactivity, vascular leak, and edema. Chronic leukotriene elevation has been also shown to be associated with pulmonary hypertension and fibrosis. We propose to block leukotriene synthesis with a 5-lipoxygenase inhibitor, zileuton. We postulate that inhibition of LT production by zileuton will be safe, feasible and significantly reduce inflammation, airway hyperreactivity, improve HbF and secondarily reduce acute sickle events. A two-step approach is proposed (1) A limited Phase I pilot study will address the safety of zileuton in children (12-18 yrs of age) and adults (18 years and older) with sickle cell disease. While zileuton is FDA approved for asthma in individuals 12 years or older, it has not been studied in the sickle population, nor has it been studied primarily for its anti-inflammatory effects in this disease. The Phase I component will therefore determine a safe dose of zileuton in sickle cell disease that has a biological effect on inflammatory endpoints and compare zileuton and leukotriene pharmacokinetics to published data on normal individuals and patients with asthma. (2) A randomized; double-blind, placebo-controlled crossover Phase II trial will determine the feasibility of chronic zileuton administration and its effect on inflammatory markers as primary endpoints. Secondary endpoints will be acute sickle events, Hb F levels, pulmonary function, and markers of pulmonary hypertension. Inflammation and pulmonary disease are two strong predictors of sickle cell disease severity and mortality. Zileuton may affect both these aspects and have an overall positive impact on disease morbidity. Lay Summary Inflammation and lung disease are important features of sickle cell disease. This study will test the ability of Zileuton, an anti-inflammatory drug licensed for treatment of asthma, to reduce inflammation in sickle cell disease and improve lung function
Keywords: 12 year old; 18 year old; Acute; acute chest syndrome; Address; Adhesions; Adult; Affect; Age; airway hyperresponsiveness; Anti-inflammatory; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Asthma; Basic Science; Biological; Blood; Blood Platelets; Blood Vessels; CCL2 gene; Child; Chronic; Clinical; Clinical Chemistry; Clinical Trials; constriction; Cross-Over Studies; cysteinyl-leukotriene; cytokine; Data; diaries; Disease; Dose; Double-Blind Method; Drug Kinetics; Edema; Endothelial Cells; Erythroid; Erythroid Cells; Event; FDA approved; Fetal Hemoglobin; Functional disorder; Goals; Growth Factor; Hospitalization; hydroxyurea; Hypoxia; IL8 gene; improved; In Vitro; Incidence; Individual; Infant; Inflammation; Inflammatory; inflammatory marker; Inflammatory Response; instrument; Intake; Knockout Mice; Laboratories; Leukocytes; Leukotriene Production; Leukotrienes; Licensing; Link; Lipoxygenase Inhibitors; Lung; Lung diseases; Lung Inflammation; macrophage; Measures; Mediating; Methodology; Monitor; monocyte; Morbidity - disease rate; Mortality Vital Statistics; neutrophil; novel; Oral; Oral Administration; Organ; Pain; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase I/II Trial; Phase II Clinical Trials; Pilot Projects; Placebo Control; Placental Growth Factor; Plasma; Population; Process; Production; Publishing; Pulmonary Emphysema; Pulmonary Fibrosis; pulmonary function; Pulmonary function tests; Pulmonary Hypertension; Quality of life; Questionnaires; Randomized; Rattus; Reactive Oxygen Species; Reperfusion Injury; Respiratory physiology; Safety; Secondary to; Serum; Severity of illness; Sickle Cell; Sickle Cell Anemia; sickling; Signal Transduction; Smooth muscle (tissue); Stimulus; Symptoms; Testing; Time; Transgenic Mice; Translating; trend; United States National Institutes of Health; Up-Regulation (Physiology); Urine; Work; Zileuton
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5U54HL070871-09_5687 (2011): $211969
Grants awarded to Malik Punam
HEMOSTATIC FACTORS AND SICKLE CELL DISEASE
Malik Punam
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Grant 1R01HL112603-01 from National Heart, Lung, And Blood Institute
Abstract: The long-term objective of this research program is to define the mechanisms by which the central hemostatic protease, thrombin, contributes to the development of sickle cell disease (SCD) pathologies. The seminal role of thrombin in hemostasis and vascular biology is underscored by the fact that this protease positively controls fibrin deposition, platelet activation, and endothelial cell (EC) signaling events via multiple substrates and receptors [e.g., protease-activated receptors, fibrinogen, factor XI, and factor XIII], as well as negatively controls further thrombin generation through the activation of protein C, a natural anticoagulant with known anti-inflammatory/cytoprotective properties. The control of thrombin activity has been intensely studied because thrombin-mediated proteolysis is fundamental to both physiological hemostasis and pathological vaso-occlusive events, including myocardial infarction, venous thrombosis and stroke. However, an additional driving force for detailed studies of thrombin and thrombin targets is that these proteins also control vascular permeability/barrier function, tissue repair, and inflammation, which together contribute to the development of multiple inflammatory diseases. Given that circulating sickle cells result in a combination of vascular damage, occlusive events and inflammatory changes, and given that local and systemic hemostatic system activation is a conspicuous feature of SCD, thrombin and thrombin targets are prime candidates to be clinically-significant modifiers of sickle cell disease pathobiology. The aims of this project center on two general hypotheses i) thrombin, as a master regulator of vascular biology, platelet/EC activation, fibrin deposition and inflammatory processes, is a major determinant of SCD pathologies, and ii) SCD-associated morbidities can be ameliorated by novel genetic or pharmacological interventions at the level of pro/thrombin and downstream thrombin substrates. These hypotheses will be tested through studies that focus on defining the importance of prothrombin in the development of multi-organ SCD pathologies and long-term survival in Berkeley sickle mice (Hba0/Hbb0 [Tg(Human HbS)]+/+)) (Aim 1); understanding the thrombin-mediated, fibrin(ogen)-dependent and fibrin(ogen)-independent mechanisms driving SCD pathologies (Aim 2); and establishing the potential benefit of thrombin-targeted pharmacological intervention in limiting SCD pathologies in mice (Aim 3). The proposed studies will provide for the first time a clear understanding of the significance of hemostatic factors in the pathogenesis of SCD and may illuminate novel therapeutic strategies for limiting SCD-induced morbidities. Sickle cell anemia affects over 100,000 Americans and millions worldwide and results in occlusion of blood vessels, pain crises, inflammation, damage to multiple organs, stroke and reduced life-expectancy. There is substantial evidence of coagulation (´clotting´) factor activation in sickle cell patients; however, the precise contributin of coagulation factors to vessel occlusion and inflammation remains unclear. The primary goal of this research is to use modern molecular genetics to develop an in-depth understanding of the contribution of key coagulation factors in sickle cell disease and explore novel treatment strategies for patients with this disease
Keywords: Affect; Alleles; American; Anti-inflammatory; Anti-Inflammatory Agents; Anticoagulants; Antisense Oligonucleotides; Automobile Driving; Binding (Molecular Function); Biology; Blood Coagulation Factor; Blood Platelets; blood vessel occlusion; Blood Vessels; clinically significant; Coagulation Process; Deposition; Development; Disease; driving force; Endothelial Cells; Event; Factor XI; Factor XIII; Fibrin; Fibrinogen; Generations; Genetic; Goals; hemoglobin A(0); Hemostatic Agents; Hemostatic function; Hepatic; Human; improved; in vivo; Inflammation; Inflammatory; inhibitor/antagonist; Integrins; Intervention; Knock-out; Leukocytes; Life Expectancy; Mediating; Molecular Genetics; Morbidity - disease rate; Mortality Vital Statistics; Mus; mutant; Myocardial Infarction; novel; novel therapeutics; Oral; Organ; Pain; PAR-1 Receptor; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Pharmacia brand of estropipate; Physiological; Platelet Activation; Play; preclinical study; Process; programs; Property; Protease Domain; Protein C; Proteinase-Activated Receptors; Proteins; Proteolysis; Prothrombin; receptor; Recombinants; Research; research study; Role; Seminal; Sickle Cell; Sickle Cell Anemia; sickling; Signal Transduction; stroke; System; Testing; Therapeutic; Thrombin; Time; treatment strategy; Variant; Vascular Permeabilities; Venous Thrombosis; Wound Healing
Relevance: Sickle cell anemia affects over 100,000 Americans and millions worldwide and results in occlusion of blood vessels, pain crises, inflammation, damage to multiple organs, stroke and reduced life-expectancy. There is substantial evidence of coagulation (´clotting´) factor activation in sickle cell patients; however, the precise contributin of coagulation factors to vessel occlusion and inflammation remains unclear. The primary goal of this research is to use modern molecular genetics to develop an in-depth understanding of the contribution of key coagulation factors in sickle cell disease and explore novel treatment strategies for patients with this disease
Project start date: 2012-01-01
Project end date: 2016-11-30
Budget start date: 1-JAN-2012
Budget end date: 30-NOV-2012
1R01HL112603-01 (2012): $382500
AMELIORATING SICKLE NEPHROPATHY AND PULMONARY HYPERTENSION
Malik Punam, Associate Professor
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Grant 1R34HL108752-01 from National Heart, Lung, And Blood Institute
Abstract: The kidney is affected in several different ways in sickle cell anemia (SCA). Children, and even infants with SCA develop a urine concentrating defect (UCD), increased glomerular filtration rate (GFR), supranormal proximal tubular function and impaired ability to excrete potassium. Also seen is hematuria (gross or microscopic) from medullary tubulo-interstitial damage. With increasing age, glomerulopathy develops, manifest initially as micro-albuminuria, then macro- albuminuria, progressing to renal failure and end stage renal disease. Kidneys and glomeruli are enlarged and GFR increased in early stages. With time, focal and segmental glomerulosclerosis, reduced GFR and end stage renal disease develops. Sickle nephropathy (SN) is present in 40-50% of adults. We have strong preliminary data on novel biomarkers on SN and animal data that supports an interventional trial with losartan to ameliorate UCD, albuminuria and pulmonary hypertension in sickle cell disease. We propose to conduct critical pilot studies in patients with SCA to guide the design of a robust phase III randomized controlled trial of losartan; and to assemble the sites, Statistics and Data Management Center (SDMC), regulatory documents, study monitoring and data management plan to ensure effective execution of a phase III multi-center study. In aim 1, we will conduct pilot studies to study the progression of SN and the feasibility of reducing/preventing SN with losartan, in order to gather critical data necessary to design a phase III randomized control trial for SN and PH. The pilot studies will help estimate feasibility of accruing patients, determine a refined duration/dose and the sample size and response rate necessary in the first two years of funding. In aim 2, we will design a multi-center phase III randomized trial of losartan for SN in the third year of funding. In aim 3, we will assemble the infrastructure to carry out a well executed multi-center trial. in the third year of funding, we will identify additional clinical sites based on eligible patients, and engage a SDMC to develop the clinical protocol, consent and assent forms, manual of operations, investigators brochure, extend the IND and prepare documents for IRB submission, establish a DSMB, data management and study monitoring plan and training materials for the study staff. We have assembled four participating sites two adult and two pediatric sites for the pilot studies Cincinnati Childrens Hospital Medical Center, University Hospital at the University of Cincinnati in Cincinnati and Nationwide Childrens Hospital and the Ohio State University Hospital in Columbus, Ohio for the pilot studies. These sites will also participate in the phase III study, while additional sites are identified and recruited, as needed based on the pilot data obtained from this planning grant. The above aims are a focused approach in this planning grant to obtain data critical for the design of a robust phase III trial, apply for RO1 funding and amass the infrastructure necessary to execute a well-designed phase III study and effectively translate research discoveries made in our laboratory to the clinic to affect effective therapeutic approaches to sickle nephropathy. The kidney is affected as early as infancy and is damaged progressively with increasing age in patients with sickle cell anemia, with nearly 40-50% of adults suffering from kidney damage (sickle nephropathy), that eventually results in end stage renal disease. Currently, there are no established therapies for preventing or reducing sickle nephropathy. With this R34 grant proposal, we plan to study the course of sickle nephropathy and perform pilot studies to treat or prevent sickle nephropathy with losartan, a drug that has been identified through our basic investigations in sickle mice. The pilot studies will help design a robust definitive clinical trial to test the therapeutic benefit of losartan in sickle nephropathy
Keywords: Adult; Affect; Age; Age-Years; Albuminuria; animal data; Antibodies; Applications Grants; base; biomarker; Blood; Blood Tests; Cardiac Catheterization Procedures; Child; Childhood; Chronic Kidney Failure; Clinic; Clinic Visits; Clinical Protocols; clinical research site; Clinical Trials; Consent; Cross-Sectional Studies; Data; data management; Defect; design; Development; Dose; End stage renal failure; Ensure; Environment; Focal Segmental Glomerulosclerosis; Funding; Generations; Glomerular Filtration Rate; Grant; Hematuria; Hospitals; Human; Hypoxia; infancy; Infant; Injury; Institutional Review Boards; interstitial; Investigation; Kidney; Kidney Diseases; Kidney Failure; Kidney Glomerulus; Laboratories; longitudinal analysis; Losartan; Lung; Manuals; Measures; Medical center; Microscopic; Molecular; Molecular Analysis; Monitor; Mus; Myocardial; Nephrons; next generation; novel; Observational Study; Ohio; older patient; operation; Pamphlets; Patients; Pattern; Pharmaceutical Preparations; Phase; phase 3 study; Phase III Clinical Trials; Physiologic intraventricular pressure; Pilot Projects; Potassium; pressure; prevent; Pulmonary Hypertension; Randomized Controlled Trials; randomized trial; Receptor, Angiotensin, Type 1; Recruitment Activity; Rectum; Research; Research Infrastructure; Research Personnel; response; Sample Size; Screening procedure; Secondary to; Sickle Cell Anemia; sickling; Signal Pathway; Signal Transduction; Site; Staging; statistics; Testing; Therapeutic; Time; Training; Translating; Tubular formation; Universities; University Hospitals; Urine; Ventricular; Walking
Relevance: The kidney is affected as early as infancy and is damaged progressively with increasing age in patients with sickle cell anemia, with nearly 40-50% of adults suffering from kidney damage (sickle nephropathy), that eventually results in end stage renal disease. Currently, there are no established therapies for preventing or reducing sickle nephropathy. With this R34 grant proposal, we plan to study the course of sickle nephropathy and perform pilot studies to treat or prevent sickle nephropathy with losartan, a drug that has been identified through our basic investigations in sickle mice. The pilot studies will help design a robust definitive clinical trial to test the therapeutic benefit of losartan in sickle nephropathy
Project start date: 2011-08-18
Project end date: 2014-06-30
Budget start date: 18-AUG-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-HL-11-009
1R34HL108752-01 (2011): $204060
PLGF-HIF1A-MIRNA AXIS IN SICKLE PULMONARY HYPERTENSION
Malik Punam
University Of Southern Californiacity: Los Angeles country: United States (us)
Grant 1R01HL111372-01 from National Heart, Lung, And Blood Institute
Abstract: Pulmonary hypertension (PHT) occurs in ~30% of patients with sickle cell anemia (SCA) and results in ~50% mortality within 2 years of diagnosis. The pathogenesis of this vasculopathy is likely multi-factorial, potentiated by hemolysis-induced impaired nitric oxide bioavailability, chronic thrombo-embolism from a procoagulant state, and increased endothelin-1 (ET-1). Our studies have shown that placenta growth factor (PlGF), an angiogenic growth factor produced in high amounts by sickle erythroid cells, induces expression of the potent pulmonary vasoconstrictor ET-1, and a procoagulant, plasminogen activator inhibitor-1 (PAI-1), from human pulmonary microvascular endothelial cells (HPMVEC). PlGF increases ET-1 and PAI-1 expression via induction of hypoxia-inducible factor-11 (HIF-11). PHT can be induced experimentally by ectopic PlGF expression in normal mice characterized by increased ET-1, as is observed in transgenic sickle mice and in SCA patients. We recently observed that PlGF-mediated induction of HIF-11 and PAI-1 in HPMVEC is post- transcriptionally regulated by three specific microRNAs (miRs). Relatively little is known of the post- transcriptional, miR-mediated, regulated expression of HIF-1a, ET-1 and PAI-1, or of the RNA-binding proteins that stabilize the mRNAs of these genes that promote PHT. Thus our overall hypothesis is that cytoplasmic RNA-binding proteins and miRNAs alter the stability of HIF-11, ET-1, and PAI-1 mRNAs, and are directly involved in the development of PHT. To address this hypothesis, in Aim 1, we will determine the post- transcriptional mechanisms which regulate PlGF-mediated expression of HIF-1a, ET-1 and PAI-1 and identify RNA binding proteins and the specific miRs involved in binding to mRNA 3´UTRs thus regulating translation of HIF-1a, ET-1, and PAI-1 mRNAs. In Aim 2, we will determine whether the genes for miRs that regulate PAI-1 expression, and are located within introns of NFYC and SKA2 genes are co-synthesized from the NFYC and SKA2 primary transcripts, or are independently transcribed from a smaller, pre-miRNA transcription unit. In Aim 3, we will demonstrate the requirement of these miRs in the regulation of HIF-11, ET-1 and PAI-1 in genetic mouse models that over-express PlGF and develop PHT. Finally, we will determine the association of plasma levels of these miRNAs to plasma PlGF, ET-1 and PAI-1 in SCA patients with and without PHT symptoms. These studies will advance our knowledge as to how RNA binding proteins and miRs regulate some of the key genes involved in sickle PHT, and how expression of these miRNAs is itself regulated. These studies will likely provide new diagnostic bio-markers for assessment of PHT, and novel therapeutic targets for a disease that currently has few or no therapeutic options. Pulmonary hypertension (PHT) is associated with high death rate among sickle cell anemia patients. We have found that genes (e.g. endothelin-1) associated with PHT are increased in these patients, and we propose to study specific microRNAs involved in their regulation
Keywords: 3` Untranslated Regions; Address; Adenovirus Vector; Binding (Molecular Function); Biological Availability; Cells; Cessation of life; Chronic; Clinical; Coronary artery; Death Rate; Development; Diagnosis; Disease; dosage; Ectopic Expression; Embolism; Endothelial Cells; Endothelin-1; Erythroid Cells; Ethanol; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Growth Factor; Hemolysis; Human; Hypoxia; hypoxia inducible factor 1; In Situ; in vivo; Inflammation; Introns; Knockout Mice; Knowledge; Laboratories; Lentivirus Vector; locked nucleic acid; Lung; Mediating; Messenger RNA; MicroRNAs; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; new therapeutic target; Nitric Oxide; novel diagnostics; Odds Ratio; Pathogenesis; Patients; Placental Growth Factor; Plasma; Plasminogen Activator Inhibitor 1; Play; Post-Transcriptional Regulation; pre-miRNA; pressure; Production; Pulmonary artery structure; Pulmonary Fibrosis; Pulmonary Hypertension; Pulmonary vessels; Regulation; Risk; RNA-Binding Proteins; Role; Sickle Cell Anemia; sickle erythroid; sickling; Smooth muscle (tissue); Symptoms; Testing; Therapeutic; Thrombosis; Transcript; transcription factor; Transgenic Organisms; Translations; Vascular Diseases; Vascular remodeling; Vasoconstrictor Agents; Wild Type Mouse
Relevance: Pulmonary hypertension (PHT) is associated with high death rate among sickle cell anemia patients. We have found that genes (e.g. endothelin-1) associated with PHT are increased in these patients, and we propose to study specific microRNAs involved in their regulation
Project start date: 2012-01-01
Project end date: 2016-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
1R01HL111372-01 (2012): $635054
Role Of Placenta Growth Factor In Sickle ACS
Malik Punam
Children´s Hospital Med Ctr (cincinnati), 3333 Burnet Ave, Cincinnati, Oh 452293039
Grant 7R01HL079916-03 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: DESCRIPTION () Acute chest syndrome (ACS), a devastating complication of sickle cell disease (SCD), is the most common cause of disease-related mortality. Nonetheless, little is known about its pathophysiology, it is diagnosed and treated only after the disease process is well underway. Work from our laboratory suggests a novel insight into the underlying pathophysiology of ACS. We show that an erythroid-cell derived angiogenic growth factor, placental growth factor (PIGF) promotes a strong inflammatory response in SCD it increases expression of VEGF, IL-1beta, IL-8, MCP-1, TNF alpha and tissue factor (TF) from monocytes via binding to VEGFR1/Flt-1. PIGF levels are increased in SCD plasma and correlate with disease severity. PIGF is inducible by hypoxia and erythropoietin (Epo), factors elevated in SCD. PIGF was recently found to strongly predict a) death or nonfatal myocardial infarction in patients presenting with chest pain and b) development and severity of bronchopulmonary dysplasia in newborns. We show that PIGF initiates downstream signaling events resulting in activation of early growth response-1 (Egr-1). Downstream targets of Egr-1 include VEGF, IL-1beta, MCP-1, TNFalpha, TF and 5-lipoxygenase (5LO), all of which increase leukocyte chemotaxis and inflammation; 5LO initiates the cascade that produces leukotrienes (LT). We show that SCD patients have evidence of reactive airway disease at baseline; PIGF increases expression of 5LO and 5LO activator protein from human pulmonary endothelial cells; and that PIGF-/- mice have a reduced inflammatory response to acute lung injury. ACS often follows an acute event, associated with a drop in hemoglobin. The latter would increase hypoxia, Epo and erythropoiesis, all of which increase PIGF production. We hypothesize that elevated PIGF, via its effect on inflammatory cytochemokines and leukotrienes results in increased inflammation and reactive airway disease at baseline in patients with SCD. Further elevations in PIGF levels during acute sickle events amplify the inflammation and reactive airway disease and contribute significantly to the cascade of events that result in ACS. Aim1 Knock out the PIGF gene in transgenic sickle mice and study their disease severity and response to acute lung injury. Aim 2 Determine whether elevated PIGF levels will predict ACS in SCD patients hospitalized for an acute event and that PLGF levels and LT levels will predict the magnitude of airway reactivity and obstructive lung disease in patients with SCD. Together, these aims are a focused approach combining basic science and clinical investigation to elucidate a mechanism that likely contributes to ACS, in order to enable early intervention in patients at high risk for ACS and target therapy at the underlying disease process. VEGFR-antagonists are in clinical trials and leukotriene blockers are FDA approved and in clinical use for asthma and could be candidates for an ACS prevention trial.
Keywords: angiogenesis factor, inflammation, lung disorder, medical complication, pathologic process, sickle cell anemiabiological signal transduction, cytokine, inhibitor /antagonist, leukotriene, lipoxygenase, lung injury, transcription factor, vascular endothelial growth factorblood test, clinical research, genetically modified animal, human subject, immunocytochemistry, laboratory mouse, lung imaging /visualization /scanning, lung lavage, spirometry, urinalysis