Thymosin Beta 4 Promotes Recovery of Peripheral Neuropathy in Diabetic Mice

胸腺素 Beta 4 促进糖尿病小鼠周围神经病变的恢复

• 批准号: 8421251
• 负责人: Lei Wang
• 金额: $ 32.3万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421251
• 关键词: Acute myocardial infarction; Affect; Aftercare; American; Amino Acids; Angiopoietin-2; Angiopoietins; Animals; Biological Process; Blood Vessels; Blood capillaries; Clinic; Clinical Data; Clinical Treatment; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Disease; Endothelial Cells; Exhibits; Functional disorder; G Actin; Genes; Hyperglycemia; In Vitro; Inflammation; Lead; Measures; Mediating; Molecular; Mus; Myocardial Infarction; Natural regeneration; Nerve; Nervous System Physiology; Neuraxis; Neurologic Dysfunctions; Neurological outcome; Neurons; Pain; Patients; Peptides; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phase; Phase I Clinical Trials; Publishing; Recovery; Regional Blood Flow; Research; Role; Schwann Cells; Signal Pathway; Small Interfering RNA; Spinal Ganglia; TIE-2 Receptor; Techniques; Testing; Therapeutic; Therapeutic Effect; Thymosin; Time; Tissues; Translations; Treatment Efficacy; Tube; angiogenesis; base; capillary; db/db mouse; density; design; diabetic; disability; effective therapy; improved; in vivo; inhibitor/antagonist; injured; innovation; insight; mouse model; neutralizing antibody; novel; polypeptide; pre-clinical; preclinical study; public health relevance; research study; sciatic nerve; stem; thymosin beta(4); vasculogenesis; wortmannin

DESCRIPTION (provided by applicant): Peripheral neuropathy is one of the major complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function in the damaged peripheral nervous system after diabetes. Thymosin ¿4 (T¿4), a major intracellular G-actin- sequestering peptide, has multiple biological functions, including promotion of remodeling of injured and damaged tissues, and increasing angiogenesis after myocardial infarction. However, the role of T¿4 in diabetic peripheral neuropathy has not been investigated. In a novel set of experiments, our data show that Tbeta4 remarkably improved sciatic nerve vascular function and peripheral nerve function in diabetic mice, indicating that T¿4 may have a beneficial effect on the clinical treatment of diabetic peripheral neuropathy. In this application, we therefore seek to investigate the mechanisms underlying the therapeutic effects of T¿4 on the treatment of diabetic peripheral neuropathy. We propose that T¿4 by improving vascular function ameliorates diabetic peripheral neuropathy. Our hypotheses are: 1. Treatment with Tbeta4 improves neurological function of peripheral neuropathy in diabetic mice. 2. The Ang/Tie2 signaling pathway mediates the therapeutic effect of T¿4 on neurovascular function in diabetic peripheral neuropathy. 3. The PI3K/Akt signaling pathway underlies the effect of Tbeta4 on Ang1/Ang2 expression. To investigate the effect of T¿4 on neurological outcome, type II diabetic mice which develop severe peripheral neuropathy will be treated with T¿4 at various time points after onset of diabetes. To investigate the molecular mechanisms that mediate Tbeta4-enhanced neurovascular function in diabetic mice, the effect of T¿4 on expression of Ang/Tie2 and activation of PI3K/Akt signaling pathway will be examined. Using pharmacological inhibitors and siRNA gene knockdown techniques, we will investigate the cause-effect of the Ang/Tie2 and PI3K/Akt signaling pathways on regulating T¿4-enhanced neurovascular function and axonal outgrowth. These studies are innovative and will provide new insight into mechanisms underlying the neurological dysfunction of diabetic peripheral neuropathy and lead to the development of a new treatment using T¿4. Relevance Statement: Peripheral neuropathy often stemming from diabetes is a major disability affecting millions of Americans. In this proposal, employing preclinical studies in the diabetic animal, I seek to develop a novel treatment for peripheral neuropath using T¿4. T¿4 is currently in a phase II clinic trial for the treatment of patients with acute myocardial infarction. In this proposal, I also elucidate the molecular mechanism by which T¿4 is therapeutically effective. This research will provide the essential pre-clinical data for translation to a phase 1 clinical trial.

描述（由申请人提供）：周围神经病变是糖尿病的主要并发症之一，迫切需要开发专门用于改善糖尿病后受损的周围神经系统的神经功能的有效治疗方法。 T¿4 (T¿4) 是一种主要的细胞内 G 肌动蛋白隔离肽，具有多种生物学功能，包括促进受伤和受损组织的重塑以及增加心肌梗塞后的血管生成。 4 在糖尿病周围神经病变中的作用尚未得到研究在一组新的实验中，我们的数据表明 Tbeta4 显着改善糖尿病小鼠的坐骨神经血管功能和周围神经功能，表明 T¿ 4 可能对糖尿病周围神经病变的临床治疗有有益作用因此，在本申请中，我们寻求研究 T¿ 治疗作用的机制。 4.关于糖尿病周围神经病变的治疗我们建议T¿ 4 通过改善血管功能改善糖尿病周围神经病变 我们的假设是： 1. Tbeta4 治疗可改善糖尿病小鼠周围神经病变的神经功能 2. Ang/Tie2 信号通路介导 T¿ 4 对糖尿病周围神经病变中神经血管功能的影响 3. PI3K/Akt 信号通路是 Tbeta4 对 Ang1/Ang2 表达影响的基础。 4 关于神经系统结果，出现严重周围神经病变的 II 型糖尿病小鼠将接受 T¿ 4 在糖尿病发病后的不同时间点，为了研究介导 Tbeta4 增强糖尿病小鼠神经血管功能的分子机制，T¿ 4 对 Ang/Tie2 表达和 PI3K/Akt 信号通路激活的影响将使用药理学抑制剂和 siRNA 基因敲低技术进行研究，我们将研究 Ang/Tie2 和 PI3K/Akt 信号通路对调节 T¿ 4-增强神经血管功能和轴突生长这些研究具有创新性，将为糖尿病周围神经病变神经功能障碍的机制提供新的见解，并导致使用 T¿ 4. 相关性声明：通常由糖尿病引起的周围神经病变是影响数百万美国人的主要残疾。在本提案中，我通过对糖尿病动物进行临床前研究，寻求开发一种使用 T 来治疗周围神经病变的新疗法。 4.T?? 4 目前正处于治疗急性心肌梗死患者的 II 期临床试验中。在本提案中，我还阐明了 T¿ 的分子机制。 4 具有治疗效果。这项研究将为转化为一期临床试验提供必要的临床前数据。