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Novel Therapeutic Strategies for Retinal Vascular Inflammation and Angiogenesis in Diabetic Retinopathy.

糖尿病视网膜病变视网膜血管炎症和血管生成的新治疗策略。

基本信息

批准号：
10213062
负责人：
Dolly Ann Padovani-Claudio
金额：
$ 19.66万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213062
关键词：
Adhesions Adult Affect Age Age related macular degeneration Alternative Therapies Blindness Blood Vessels Cell model Cells Chemotaxis Child Childhood Clinical Trials Collaborations Complex Complications of Diabetes Mellitus Conditioned Culture Media Data Development Diabetes Mellitus Diabetic Retinopathy Disease Drug usage Effectiveness Endothelial Cells Event Extravasation Eye Fatty Acids Functional disorder Funding Future Genes Genetic Polymorphism Glaucoma Glucose Goals Hemorrhage Hispanics Homologous Gene Human Hyperglycemia Hypoxia IL8 gene IL8RA gene IL8RB gene In Vitro Incidence Inflammation Inflammatory Interleukin 8A Receptor Interleukin-1 beta Interleukin-8 Leukocytes Leukostasis Ligands Malignant Neoplasms Measures Mentors Mentorship Metabolic Metabolic syndrome Modeling Muller&apos s cell Neuroglia Obesity Ophthalmologist Ophthalmology Orphan Drugs Oxygen Palmitic Acids Pathogenesis Pathogenicity Pathologic Pathology Patient Care Patients Permeability Pharmaceutical Preparations Population Positioning Attribute Predisposition Prevalence Primary Cell Cultures Process Promoter Regions Reaction Research Research Personnel Resistance Retina Retinal Diseases Retinal Edemas Retinal Neovascularization Severities Signal Pathway Signal Transduction Small Interfering RNA Stimulus Streptozocin System TNF gene Testing Therapeutic Training Tube Up-Regulation VEGFR inhibition Vascular Endothelial Cell Vascular Endothelial Growth Factors Vision angiogenesis base body system career cell motility chemokine chemokine receptor clinical practice cytokine design diabetic effective therapy experience glial activation in vitro Assay in vivo inhibitor/antagonist monolayer mouse model neutralizing antibody novel novel therapeutic intervention novel therapeutics patient population preclinical trial prevent receptor response retinal angiogenesis skills standard of care vascular inflammation vision development

项目摘要

PROJECT SUMMARY/ABSTRACT As a pediatric ophthalmologist concerned by the growing incidence of obesity, metabolic syndrome, and diabetes in the pediatric population, especially in Hispanic patients, I have chosen to focus my research on diabetic retinopathy. Inflammation and angiogenesis herald the development of vision-threatening complications of diabetic retinopathy (DR), including retinal edema, hemorrhages, glaucoma and detachments. Vascular endothelial growth factor (VEGF) inhibitors are the standard of care drugs used to treat vision threatening DR complications; however, their effectiveness is limited to certain patient populations and no alternative therapies have emerged into clinical practice. The chemokine CXCL8, which is known to affect pathologic mechanisms associated with DR, accumulates in the eyes of diabetics and its levels correlate with DR progression. However, we do not fully understand the functional implications of its induction and subsequent accumulation. We have found that multiple pro-inflammatory and pro-angiogenic molecules associated with DR induce CXCL8 in human retinal cells, and that CXCL8 can affect human retinal endothelial cell responses associated with DR onset and progression. I believe that CXCL8 is a key intermediary at the juncture of multiple signaling pathways that regulate and promote both early and late events in DR pathology, including VEGF signaling. Therefore, CXCL8 receptors may be ideal targets for novel DR therapies. Several inhibitors of CXCL8 receptors are in clinical trials for non-ocular conditions, yet their potential to interfere with mechanisms of DR in the retina has not been explored. I believe that there is value in testing these inhibitors in clinical trials and repurposing them to treat patients with DR. However, before pursuing that goal, the significance of CXCL8 induction in the eye in relation to mechanisms of DR pathology (Aim 1) and the value of these inhibitors to interfere with those mechanisms (Aim 2) must be rigorously evaluated. I intend to do this using a stepwise approach complimenting human primary cell culture-based in vitro assays (Müller glia and vascular endothelial cells, Aim1), with in vivo mouse models of DR-associated pathologic events (Streptozotocin-induced diabetes and oxygen-induced retinopathy models, Aim 2). Confirming the ability of commercially-available CXCL8 receptor inhibitors to block DR-relevant pathogenic processes would affirm their therapeutic potential to treat DR, and inform the design of future pre-clinical and clinical trials. This mentored experience will allow me to generate pilot data to successfully compete for R-level funding, to advance the understanding of DR pathophysiology, and to accelerate the development of new DR therapies, therefore promoting my independence as a clinician investigator. The skills, collaborative relationships, and data acquired by the execution of this proposal and its training plan, along with my ophthalmology training, should optimally position my career for successful long term funding and significant impact on patient care.

项目总结/文摘