Cell therapy for diabetic peripheral 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）和糖尿病神经病变（DN）。PAD通常以下肢动脉闭塞性疾病为特征，当进展到严重肢体缺血阶段时，往往会导致腿部截肢。由于糖尿病中的晚期PAD经常影响小血管，因此常规经皮介入和手术治疗在许多情况下无效。糖尿病神经病变（DN）是糖尿病最常见的并发症，影响60%的糖尿病患者。DN的特征在于对神经血管系统以及神经元细胞的损伤。尽管这些使人衰弱的疾病的发病率不断增加，但目前没有有效治疗这些病症的治疗方法。越来越多的证据表明，骨髓来源的内皮祖细胞（EPCs）可以通过诱导新生血管形成来治疗各种心血管疾病和糖尿病肾病。然而，研究已经报道，源自糖尿病受试者的EPC是功能障碍的，因此自体细胞疗法可能具有有限的治疗效果。最近的证据表明，即使在实现葡萄糖控制后，糖尿病也可能导致长期并发症，并且表观遗传染色质改变可能是靶细胞代谢记忆的基础。已经取得的其他进展显示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，生物工程方法已被用于克服细胞移植的缺点。因此，我们的目标是研究糖尿病EPCs的表观遗传染色质变化，并用小分子表观遗传调节剂和生物材料重新编程和/或工程化糖尿病EPCs以增强或恢复其功能。我们将最终确定它们对糖尿病PAD和DN的良好动物模型的治疗效果。我们预计，这项研究将产生新的见解的染色质改变的内皮祖细胞在糖尿病和建议的潜在治疗效用的修饰内皮祖细胞治疗各种糖尿病相关的神经血管并发症在自体的方式。鉴于EPCs的安全性，一旦本研究确定了疗效，这种方法可以很容易地转化为初步临床试验。 公共卫生相关性：尽管糖尿病神经血管并发症如晚期外周动脉疾病（PAD）或严重肢体缺血和糖尿病神经病变（DN）的发病率不断增加，但尚未有治疗方法有效治疗这些疾病。越来越多的证据表明，骨髓来源的内皮祖细胞（EPCs）是有效的治疗各种心血管疾病和DN诱导血管形成和保护进一步的神经损伤;然而，研究报告，EPCs来自糖尿病受试者是功能障碍，因此自体细胞治疗可能有有限的治疗效果。因此，我们的目标是确定糖尿病EPCs的表观遗传变化，并重新编程和/或工程这些糖尿病EPCs与小分子化学品和生物材料，以增强或恢复其功能，治疗糖尿病神经血管并发症。

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.