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Principal Investigator: Akrit Singh Sodhi
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $470,039
Funding agency: National Eye Institute
PROJECT SUMMARY:
Diabetes accounts for 10% of healthcare spending in the United States. A growing portion of this cost is
spent on treatments for diabetic eye disease, the leading cause of blindness among working-age adults in the
developed world. Early nonproliferative diabetic retinopathy (NPDR) is driven by hyperglycemia that promotes
injury to the retina microvasculature. On the other hand, proliferative diabetic retinopathy (PDR) develops after
progressive microvascular damage ultimately results in retinal ischemia and subsequent hypoxia, driving the
expression of factors that promote angiogenesis. Several labs have demonstrated that the regulation of
angiogenic genes in late stages of diabetic eye disease is mediated by the transcription factor, hypoxia-inducible
factor (HIF) in patients with retinal ischemia and PDR. However, a role for HIF in early stages of diabetic
retinopathy (DR) is unclear.
We recently demonstrated that transient episodes of hypoglycemia promotes the nuclear accumulation
of HIF-1α, independent of hypoxia. This, in turn, results in an increase in expression of the angiogenic mediators
that promote the growth of abnormal, leaky vessels in patients with DR. More recently, we have observed that
activation of the p38 signaling pathway is necessary for HIF-1α accumulation in response to transient
hypoglycemia. These observations implicate the p38/HIF-1 pathway in early. Events in the promotion of DR
progression, independent of retinal ischemia. Based on these observations, we propose that inhibiting the
p38/HIF-1α pathway will be an effective approach to prevent the progression of DR. In this proposal, we use a
combination of genetic and pharmacologic approaches to evaluate the safety and efficacy of therapies that target
HIF-1 (SA1) or p38 (SA2) to prevent the progression of DR.
Terms: <21+ years old><Adult><Adult Human><Age><American><Automobile Driving><Background Diabetic Retinopathy><Basal Transcription Factor><Basal transcription factor genes><Blindness><Blood Serum><Blood Vessels><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><Cell Body><Cells><Clinical><Clinical Trials><Complications of Diabetes Mellitus><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><D-Glucose><Development><Dextrose><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Complications><Diabetic Retinopathy><Disease><Disorder><Dose><Drop-seq><Early treatment><Equilibrium><Erythrocyte/Hepatoma Glucose Transporter><Event><Exposure to><Eye diseases><GLUT><GLUT1><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Glia><Glial Cells><Glucose><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucose Transporter 1><Glycated Hemoglobins><Glycohemoglobin A><Glycolysis><Glycosylated Hemoglobin><Glycosylated hemoglobin A><Growth><HIF 1><HIF-1 protein><HIF1><HIF1 protein><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Healthcare><Hemoglobin A(1)><Humulin R><Hyperglycemia><Hypoglycemia><Hypoxia><Hypoxia Inducible Factor><Hypoxic><Injections><Injury><Insulin><Kolliker's reticulum><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><Mediating><Mediator><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 14><Modeling><Molecular><Molecular Target><Muller glia><Muller's cell><Murine><Mus><Mxi2><Müller cell><Müller glia><Neuroglia><Neuroglial Cells><Non-Polyadenylated RNA><Non-Proliferative Diabetic Retinopathy><Non-neuronal cell><Nonneuronal cell><Novolin R><Nuclear><O element><O2 element><Oxygen><Oxygen Deficiency><Pathologic><Pathway interactions><Patients><Phase><Physiologic><Physiological><Prevention><Prevention therapy><RNA><RNA Gene Products><Regular Insulin><Regulation><Reporting><Retina><Ribonucleic Acid><Role><SAPK2A><SLC2A1><SLC2A1 gene><Safety><Serum><Sight><Signal Pathway><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Stress-Activated Protein Kinase 2A><Therapeutic><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Treatment Efficacy><United States><Vision><adulthood><ages><angiogenesis><balance><balance function><cost><developmental><diabetes><diabetes control><diabetes mellitus control><diabetic><driving><droplet sequencing><early therapy><eye disorder><glycemic control><health care><hemoglobin A1c><high risk><hyperglycemic><hypoglycemic><hypoglycemic episodes><hypoxia inducible factor 1><in vivo Model><inhibitor><injuries><injury to the vasculature><insight><intervention efficacy><macrovascular complication><macrovascular disease><nerve cement><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ocular disease><ocular disorder><ontogeny><ophthalmopathy><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pathway><pharmacologic><prevent><preventing><proliferative diabetic retinopathy><response><retina ischemia><retinal ischemia><retinal neuron><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><transcription factor><vascular><vascular injury><vision loss><visual function><visual loss>