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Dyslipidemia and Diabetic Retinopathy

血脂异常和糖尿病视网膜病变

基本信息

批准号：
9037380
负责人：
Julia V Busik
金额：
$ 38.82万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037380
关键词：
Address Affect Angiogenic Factor Binding Blood Vessels Bone Marrow CD34 gene Cells Ceramides Chimera organism Chronic Combined Modality Therapy Complications of Diabetes Mellitus Data Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Dyslipidemias Elements Endothelial Cells Enzymes Extravasation Functional disorder Funding Gene Targeting Genes Genetic Transcription Health Human Hyperglycemia In Vitro Inflammation Inflammatory Injury Lipids Mediating Membrane Fluidity Metabolism MicroRNAs Modeling Muller&apos s cell Pathology Pathway interactions Permeability Pharmacotherapy Prevention Production RNA annealing Regulation Retina Retinal Rodent Role Sphingolipids Sphingomyelins Stem cells Streptozocin Structure of retinal pigment epithelium Testing Therapeutic Transcript Transgenic Mice Translations Untranslated RNA Vascular Endothelial Growth Factors Vascular Permeabilities Vision acid sphingomyelinase base cytokine diabetic endothelial dysfunction gain of function in vivo inhibitor/antagonist loss of function migration overexpression promoter public health relevance repaired therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a sight threatening disease with few therapeutic options. Low-grade chronic inflammation in the retina [1-8] and inadequate vascular repair due to compromised function of the bone marrow (BM)-derived circulating angiogenic cells (CACs) [9-12] contribute to progression of retinal vascular pathology. A number of hyperglycemia- and dyslipidemia- activated pathways promoting the increase of pro-inflammatory cytokines, pro-inflammatory lipids and pro-angiogenic factors leading to retinal endothelial cell and CAC dysfunction have been identified [2-4, 6, 9, 10, 13-25]. Dysregulation of these pathways is hypothesized to involve microRNAs (miRNAs). These small non-coding RNAs anneal imperfectly to target genes and simultaneously control translation and transcription [26]. Several miRNA classes have been shown to contribute to diabetes and diabetic complications [27, 28], including diabetic retinopathy [29]. Studies during the previous funding period identified miR-15a as a key regulator of both pro-inflammatory and pro-angiogenic pathways. miR-15a accomplishes these tasks through direct binding and inhibition of the central enzyme in the sphingolipid pathway, acid sphingomyelinase (ASM), and inhibition of VEGF-A. Based on these data, we hypothesize that miRNAs represent therapeutic targets for prevention and treatment of DR by simultaneously regulating pro-inflammatory and pro-angiogenic pathways in the retina and CACs. We will address the role of miR-15a in DR with the following Specific Aims. Specific aim 1: To test the hypothesis that the decrease in miR-15a observed in diabetes contributes to increased ASM activity and VEGF-A production leading to pro- inflammatory changes, increased permeability and endothelial dysfunction in the retina. Specific aim 2: To test the hypothesis that decrease in miR-15a in diabetes leads to ASM activation and ceramide production resulting in decreased membrane fluidity of bone marrow-derived CACs. Decreased membrane fluidity results in entrapment of progenitor cell in the bone marrow and reduced repair function due to impaired migration and extravasation capacity. Manipulation of miR-15a to simultaneously control sphingolipid metabolism and pro-angiogenic pathways through direct regulation of ASM and VEGF-A production in the diabetic retina and BM should provide a unique and effective "combination therapy" approach that will add to the pharmacological armamentarium of drug therapies for diabetic retinopathy.