Cell therapy for diabetic peripheral neurovascular complications

细胞疗法治疗糖尿病周围神经血管并发症

基本信息

批准号：
8241514
负责人：
Xiaodong Cheng
金额：
$ 613.9万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241514
关键词：
Accounting Address Affect Amputation Animal Model Arterial Occlusive Diseases Autologous Biocompatible Materials Bioinformatics Biological Biological Assay Biomedical Engineering Blood Vessels Bone Marrow Cardiology Cardiovascular Diseases Cell Survival Cell Therapy Cell Transplantation Cells Chemicals Chromatin Clinical Clinical Trials Complications of Diabetes Mellitus DNA Methylation Diabetes Mellitus Diabetic Neuropathies Disease Disease Progression Engineering Engraftment Epigenetic Process Ethylene Glycols Extracellular Matrix Functional disorder Gel Gene Expression Gene Targeting Genes Goals Hindlimb Histones Human Hydrogels Image Incidence Injectable Ischemia Lasers Lead Leg Limb structure Lower Extremity Magnetic Resonance Imaging Measurement Memory Metabolic Methylation Molecular Monitor Morbidity - disease rate Mus Neurology Neurons Operative Surgical Procedures Patients Peripheral Peripheral Nervous System Diseases Peripheral arterial disease Phenotype Physiological Regenerative Medicine Reporting Research Personnel Role Safety Staging Stem cells Testing Therapeutic Therapeutic Effect Translating base blood glucose regulation chromatin remodeling diabetic diabetic patient ethylene glycol genome-wide global health histone modification in vivo innovation insight member neovascularization next generation novel relating to nervous system research study small molecule stem cell biology structural biology

项目摘要

DESCRIPTION (provided by applicant): Diabetes is a rapidly growing global health problem. Patients with diabetes are frequently affected by neuro-vascular complications such as peripheral arterial disease (PAD) and diabetic neuropathy (DN). PAD is usually characterized by occlusive arterial disease of the lower extremities, and when advanced into the critical limb ischemia stage, can often lead to leg amputation. As advanced PAD in diabetes frequently affects small vessels, conventional percutaneous intervention and surgical treatment are ineffective in many cases. Diabetic neuropathy (DN) is the most common complication of diabetes, affecting 60% of diabetic patients. DN is characterized by damage to the neural vasculature as well as to neuronal cells. Despite the continuous increase in the incidence of these debilitating diseases, no current treatments effectively treat these conditions. Growing evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) are effective in treating various cardiovascular diseases and DN by inducing neovascularization. However, studies have reported that EPCs derived from diabetic subjects are dysfunctional, and therefore autologous cell therapy may have limited therapeutic effects. Recent evidence has suggested that even after achieving glucose control, diabetes can lead to long-term complications, and epigenetic chromatin alterations may underlie this metabolic memory of target cells. Other advances have been made that show the ability of small molecules to induce chromatin remodeling of affected genes and alter gene expression and cell phenotype. In addition, a bioengineering approach has been used to overcome the shortcomings of cell transplantation. Accordingly, we aim to investigate epigenetic chromatin changes in diabetic EPCs, and to reprogram and/or engineer diabetic EPCs with small molecular epigenetic regulators and biomaterial to enhance or restore their function. We will finally determine their therapeutic effects on well-established animal models of diabetic PAD and DN. We anticipate that this study will yield novel insight into the chromatin alterations of the EPCs in diabetes and suggest the potential therapeutic utility of modified EPCs for treating various diabetes-related neurovascular complications in an autologous manner. Given the safety of EPCs, this approach can be easily translated into a pilot clinical trial once the efficacy is established by this study. PUBLIC HEALTH RELEVANCE: Despite the ever-growing incidence of diabetic neuro-vascular complications such as advanced peripheral arterial disease (PAD) or critical limb ischemia, and diabetic neuropathy (DN), no treatments have yet to effectively treat these diseases. Growing evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) are effective in treating various cardiovascular diseases and DN by inducing vessel formation and protection from further neural damage; however, studies have reported that EPCs derived from diabetic subjects are dysfunctional, and therefore autologous cell therapy may have limited therapeutic effects. Accordingly we aim to identify the epigenetic changes of diabetic EPCs, and reprogram and/or engineer these diabetic EPCs with small molecular chemicals and biomaterials to enhance or restore their function for treating diabetic neurovascular complications.

描述（由申请人提供）：糖尿病是一个快速增长的全球健康问题。糖尿病患者经常受到神经血管并发症的影响，例如外周动脉疾病（PAD）和糖尿病神经病（DN）。 PAD通常以下肢的闭合动脉疾病为特征，并且在进入临界肢体缺血阶段时，通常会导致腿部截肢。由于糖尿病的晚期垫经常会影响小血管，因此在许多情况下，常规经皮干预和手术治疗无效。糖尿病神经病（DN）是糖尿病最常见的并发症，影响60％的糖尿病患者。 DN的特征是对神经脉管系统以及神经元细胞的损害。尽管这些使人衰弱的疾病的发生率不断增加，但目前没有有效治疗这些疾病。越来越多的证据表明，骨髓来源的内皮祖细胞（EPC）可有效治疗各种心血管疾病，并通过诱导新血管形成。然而，研究报告说，源自糖尿病患者的EPC是功能障碍，因此自体细胞疗法可能具有有限的治疗作用。最近的证据表明，即使在实现葡萄糖控制后，糖尿病也会导致长期并发症，而表观遗传染色质的改变也可能是靶细胞代谢记忆的基础。已经取得了其他进步，表明小分子诱导受影响基因的染色质重塑并改变基因表达和细胞表型的能力。此外，已经使用了一种生物工程方法来克服细胞移植的缺点。因此，我们旨在研究糖尿病EPC的表观遗传染色质变化，并重新编程和/或具有小分子表观遗传调节剂和生物材料的糖尿病EPC，以增强或恢复其功能。我们最终将确定它们对糖尿病垫和DN的良好动物模型的治疗作用。我们预计这项研究将对糖尿病中EPC的染色质改变产生新的见解，并提出改良的EPC的潜在治疗用途，以自体以自体方式治疗各种糖尿病相关的神经血管并发症。鉴于EPC的安全性，一旦这项研究确定了功效，这种方法就可以轻松地转化为试点临床试验。公共卫生相关性：尽管糖尿病神经血管并发症的发生率不断增长，例如晚期外周动脉疾病（PAD）或临界肢体缺血以及糖尿病神经病（DN），但没有治疗尚未有效治疗这些疾病。越来越多的证据表明，骨髓来源的内皮祖细胞（EPC）可有效治疗各种心血管疾病，并通过诱导血管形成并保护侵害进一步的神经损害，并通过DN进行DN；然而，研究报告说，源自糖尿病患者的EPC是功能障碍，因此自体细胞疗法可能具有有限的治疗作用。因此，我们旨在确定糖尿病EPC的表观遗传变化，并用小分子化学物质和生物材料重新编程和/或工程师这些糖尿病EPC，以增强或恢复其在治疗糖尿病神经血管并发症方面的功能。