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:
  • 金额:
    $ 613.9万
  • 依托单位:
  • 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

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,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,当进展到严重的肢体缺血阶段时,往往会导致腿部截肢。由于糖尿病晚期PAD经常累及小血管,传统的经皮介入和手术治疗在许多情况下是无效的。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 的特征是神经脉管系统和神经元细胞受损。尽管这些使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。越来越多的证据表明,骨髓来源的内皮祖细胞 (EPC) 通过诱导新血管形成可有效治疗各种心血管疾病和 DN。然而,研究报告称,来自糖尿病受试者的EPCs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并发症,而表观遗传染色质改变可能是靶细胞这种代谢记忆的基础。其他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,生物工程方法已被用来克服细胞移植的缺点。因此,我们的目标是研究糖尿病 EPC 中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对糖尿病 EPC 进行重新编程和/或改造,以增强或恢复其功能。我们最终将确定它们对已建立的糖尿病 PAD 和 DN 动物模型的治疗效果。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,并提出修饰的 EPC 在以自体方式治疗各种糖尿病相关神经血管并发症方面的潜在治疗效用。考虑到 EPC 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试点临床试验。 公共健康相关性:尽管糖尿病神经血管并发症(例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))的发病率不断增加,但尚未有有效治疗这些疾病的治疗方法。越来越多的证据表明,骨髓来源的内皮祖细胞 (EPC) 通过诱导血管形成和防止进一步的神经损伤,可有效治疗各种心血管疾病和 DN;然而,研究报告称,来自糖尿病受试者的EPCs功能失调,因此自体细胞疗法的治疗效果可能有限。因此,我们的目标是识别糖尿病 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/或改造这些糖尿病 EPC,以增强或恢复其治疗糖尿病神经血管并发症的功能。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(4)

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Xiaodong Cheng其他文献

Xiaodong Cheng的其他文献

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{{ truncateString('Xiaodong Cheng', 18)}}的其他基金

Mutual reinforcement between somatic mutations and transcription factors in clonal hematopoiesis
克隆造血中体细胞突变和转录因子之间的相互强化
  • 批准号:
    10601791
  • 财政年份:
    2023
  • 资助金额:
    $ 613.9万
  • 项目类别:
Epigenetic regulations of DNA and histone methylation and deMethylation: Structures and Mechanisms
DNA 和组蛋白甲基化和去甲基化的表观遗传调控:结构和机制
  • 批准号:
    10318519
  • 财政年份:
    2020
  • 资助金额:
    $ 613.9万
  • 项目类别:
Epigenetic regulations of DNA and histone methylation and deMethylation: Structures and Mechanisms
DNA 和组蛋白甲基化和去甲基化的表观遗传调控:结构和机制
  • 批准号:
    10544993
  • 财政年份:
    2020
  • 资助金额:
    $ 613.9万
  • 项目类别:
Epigenetic regulations of DNA and histone methylation and deMethylation: Structures and Mechanisms
DNA 和组蛋白甲基化和去甲基化的表观遗传调控:结构和机制
  • 批准号:
    10794474
  • 财政年份:
    2020
  • 资助金额:
    $ 613.9万
  • 项目类别:
Histone Lysine deMethylation: Structures, Inhibitions and Mechanisms
组蛋白赖氨酸去甲基化:结构、抑制和机制
  • 批准号:
    8861037
  • 财政年份:
    2015
  • 资助金额:
    $ 613.9万
  • 项目类别:
Histone Lysine deMethylation: Structures, Inhibitions and Mechanisms
组蛋白赖氨酸去甲基化:结构、抑制和机制
  • 批准号:
    9039106
  • 财政年份:
    2015
  • 资助金额:
    $ 613.9万
  • 项目类别:
STRUCTURAL STUDY OF EPIGENETIC MODIFICATIONS
表观遗传修饰的结构研究
  • 批准号:
    8361728
  • 财政年份:
    2011
  • 资助金额:
    $ 613.9万
  • 项目类别:
DNA Methylation: Structures, Functions, and Regulation
DNA 甲基化:结构、功能和调控
  • 批准号:
    8123687
  • 财政年份:
    2010
  • 资助金额:
    $ 613.9万
  • 项目类别:
Generation of Induced Pluripotent Stem Cells with Novel Small Molecule Regulator
使用新型小分子调节剂生成诱导多能干细胞
  • 批准号:
    7836639
  • 财政年份:
    2010
  • 资助金额:
    $ 613.9万
  • 项目类别:
Histone Lysine Methylation: Structures and Functions
组蛋白赖氨酸甲基化:结构和功能
  • 批准号:
    8124458
  • 财政年份:
    2010
  • 资助金额:
    $ 613.9万
  • 项目类别:

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