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

• 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
• 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

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(申请人提供)：糖尿病是一个迅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，如周围动脉病变(PAD)和糖尿病神经病变(DN)。PAD通常以下肢动脉闭塞性疾病为特征，当进展到严重的肢体缺血阶段时，往往会导致小腿截肢。由于糖尿病晚期PAD常累及小血管，常规的经皮介入治疗和手术治疗在许多情况下无效。糖尿病神经病变是糖尿病最常见的并发症，影响60%的糖尿病患者。糖尿病肾病的特点是对神经血管和神经细胞的损伤。尽管这些令人衰弱的疾病的发病率不断增加，但目前还没有有效的治疗方法来治疗这些疾病。越来越多的证据表明，骨髓来源的内皮祖细胞可通过诱导新生血管来治疗各种心血管疾病和糖尿病肾病。然而，已有研究报道糖尿病患者来源的内皮祖细胞功能失调，因此自体细胞疗法的治疗效果可能有限。最近的证据表明，即使在实现血糖控制后，糖尿病也可能导致长期的并发症，而表观遗传的染色质改变可能是靶细胞代谢记忆的基础。其他的进展表明小分子能够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。此外，还使用了一种生物工程方法来克服细胞移植的缺点。因此，我们的目标是研究糖尿病内皮祖细胞的表观遗传学染色质变化，并利用小分子表观遗传调节因子和生物材料重新编程和/或改造糖尿病内皮细胞，以增强或恢复其功能。我们将最终确定它们在糖尿病PAD和糖尿病肾病动物模型上的治疗效果。我们预计，这项研究将为糖尿病患者内皮祖细胞的染色质改变提供新的见解，并提示改良后的内皮祖细胞以自体方式治疗各种糖尿病相关神经血管并发症的潜在治疗作用。考虑到内皮祖细胞的安全性，一旦这项研究确定了疗效，这种方法很容易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病率不断上升，如晚期外周动脉疾病(PAD)或严重肢体缺血，以及糖尿病神经病变(DN)，但目前还没有有效的治疗方法来治疗这些疾病。越来越多的证据表明，骨髓来源的内皮祖细胞通过诱导血管形成和防止进一步的神经损伤而有效地治疗各种心血管疾病和糖尿病肾病；然而，有研究报道来自糖尿病患者的内皮祖细胞功能障碍，因此自体细胞治疗的疗效可能有限。因此，我们的目标是识别糖尿病内皮祖细胞的表观遗传学变化，并用小分子化学物质和生物材料对这些糖尿病内皮细胞进行重新编程和/或工程，以增强或恢复它们治疗糖尿病神经血管并发症的功能。