Adipose Stem Cells for Diabetic Retinopathy

脂肪干细胞治疗糖尿病视网膜病变

• 批准号: 8487411
• 负责人: IRA M HERMAN
• 金额: $ 47.68万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487411
• 关键词: Activities of Daily Living; Acute; Adipose tissue; Adopted; Adult; Age; American; Antibodies; Apoptosis; Biological Assay; Blindness; Blood; Blood Circulation; Blood Vessels; Blood capillaries; CSPG4 gene; Cell Communication; Cell Differentiation process; Cell physiology; Cell surface; Cells; Characteristics; Chronic; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Disease Progression; Dropout; Endothelial Cells; Endothelium; Event; Exhibits; Extravasation; Fibroblast Growth Factor Receptors; Fostering; Growth; Harvest; Homeostasis; Human; Hyperglycemia; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Injury; Intervention; Lead; Liver; Lung; Measures; Mediator of activation protein; Mesentery; Microaneurysm; Modeling; Monitor; Mus; Natural regeneration; Organ; Outcome; Oxygen; Pathologic; Pathologic Neovascularization; Pathology; Patients; Pericytes; Permeability; Platelet-Derived Growth Factor; Population; Prevalence; Property; Protein-Serine-Threonine Kinases; Recurrence; Retina; Retinal; Retinal Diseases; Retinal Edemas; Retinal Neovascularization; Signal Transduction; Smooth Muscle Actin Staining Method; Sorting - Cell Movement; Spleen; Stem cells; Streptozocin; Surface; Symptoms; Testing; Time; Vascular Diseases; Vascular Permeabilities; Vascularization; Venous; Visual; Work; adult stem cell; base; blind; calponin; capillary; cell growth; cytokine; design; diabetes risk; diabetic; diabetic patient; in vivo; macular edema; neovascularization; novel; novel strategies; prevent; proliferative diabetic retinopathy; relating to nervous system; repaired; response; retina blood vessel structure; retinal ischemia; stem cell therapy; trafficking; tumorigenesis; tyrosine receptor

DESCRIPTION (provided by applicant): Prevalence estimates suggest that 23.6 million US residents have diabetes, and this number is predicted to double over the next thirty years. Diabetic retinopathy is the leading cause of blindness, and occurs in 100% of Type 1 and 60% of Type 2 diabetic patients within 20 years of diagnosis, and more than 12,000 patients become blind each year due to ocular complications from this disease. The underlying cause of diabetic retinopathy is damage to the retinal microvasculature from chronic hyperglycemia leading to increased vascular permeability and vascular occlusion. Recent evidence has shown that all of these events follow from the initial loss of pericytes on microvessels in the retina, which makes endothelial cells susceptible to diabetic conditions that result in the microaneurysms, venous changes, retinal capillary loss, and retinal ischemia. We propose to target the aberrant loss of pericytes by developing and evaluating a novel adult stem cell therapy that, we hypothesize, will supplement the native pericyte population and maintain microvessel homeostasis, thereby preventing the downstream effects that ultimately lead to macular edema. We have recently shown that a sub-population of adult human adipose-derived stem cells (hASCs) spontaneously differentiates into pericytes when injected in vivo, and in so doing, stabilizes the microvascular endothelium. We will test the hypothesis that cultured ASCs contain a sub-population of pericytes (or, pericyte precursors) that exhibits the intracellular signaling machinery, contractil properties, and functional abilities to diminish microvascular leakage, reduce capillary dropout, and prevent pathologic angiogenic induction and/or EC hyper-proliferation in three relevant murine models: oxygen-induced retinopathy (OIR), streptozocin induced diabetes (STZ), and Akimba whose pathological outcomes are related to early non-proliferative and late proliferative aspects of human DR. Our strategy is to supplement the endogenous pericyte population in order to enhance endothelial stability and prevent vessel loss. Therefore, we have designed three aims to evaluate the putative pericyte capacity of hASCs in the retina. Aim 1: Identify the hASC subpopulation(s) capable of becoming functional pericytes in vitro; Aim 2: Determine the capacity of hASCs to stabilize retinal vessels against acute (OIR) and chronic (STZ & Akimba) vascular insults; Aim 3: Determine the capacity of hASCs to enhance retinal revascularization and stabilize aberrant neovascularization following acute (OIR) and chronic (STZ & Akimba) vascular insults.

描述（由申请人提供）：患病率估计表明，2360万美国居民患有糖尿病，预计这一数字在未来30年内将翻一番。糖尿病视网膜病变是失明的主要原因，并且在诊断后的20年内发生在100%的1型和60%的2型糖尿病患者中，并且每年超过12，000名患者由于这种疾病的眼部并发症而失明。糖尿病视网膜病变的根本原因是慢性高血糖症对视网膜微血管系统的损伤，导致血管通透性增加和血管闭塞。最近的证据表明，所有这些事件都源于视网膜微血管上周细胞的初始损失，这使得内皮细胞对糖尿病状况敏感，从而导致微动脉瘤、静脉变化、视网膜毛细血管损失和视网膜缺血。我们建议通过开发和评估一种新的成体干细胞疗法来靶向周细胞的异常损失，我们假设该疗法将补充天然周细胞群体并维持微血管稳态，从而防止最终导致黄斑水肿的下游效应。我们最近已经表明，成人脂肪源性干细胞（hASCs）的亚群在体内注射时自发分化为周细胞，并在这样做时，稳定微血管内皮。我们将检验培养的ASCs含有周细胞亚群的假设（或，周细胞前体），其在三种相关鼠模型中表现出细胞内信号传导机制、收缩性质和减少微血管渗漏、减少毛细血管脱落和防止病理性血管生成诱导和/或EC过度增殖的功能能力：氧诱导的视网膜病变（OIR），链脲佐菌素诱导的糖尿病（STZ），和Akimba，其病理结果与早期非-我们的策略是补充内源性周细胞群以增强内皮稳定性防止船舶损失。因此，我们设计了三个目标来评估视网膜中hASC的假定周细胞能力。目标1：鉴定能够在体外成为功能性周细胞的hASC亚群;目的2：确定hASC针对急性（OIR）和慢性（STZ & Akimba）血管损伤稳定视网膜血管的能力;目的3：确定hASC在急性（OIR）和慢性（STZ & Akimba）血管损伤后增强视网膜血管再生和稳定异常新生血管形成的能力。