Thymosin Beta4 Promotes the Recovery of Peripheral neuropathy in Type II Diabetic

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。迫切需要开发专门设计用于改善糖尿病后受损周围神经系统的神经功能的有效治疗方法。胸腺素4（T）4）是一种主要的细胞内G-肌动蛋白螯合肽，具有多种生物学功能，包括促进损伤和受损组织的重塑，以及增加心肌梗死后的血管生成。然而，T4在糖尿病周围神经病变中的作用尚未研究。在一组新的实验中，我们的数据显示Tbeta 4显著改善了糖尿病小鼠的坐骨神经血管功能和外周神经功能，表明T4可能对糖尿病周围神经病变的临床治疗具有有益的作用。因此，在本申请中，我们试图研究T4治疗糖尿病周围神经病变的治疗作用的机制。我们认为T4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.用Tbeta 4治疗改善糖尿病小鼠中周围神经病变的神经功能。2. Ang/Tie 2信号通路介导T4对糖尿病周围神经病变神经血管功能的治疗作用3. PI 3 K/Akt信号通路是Tbeta 4对Ang 1/Ang 2表达影响的基础。为了研究T4对神经学结果的影响，将在糖尿病发作后的不同时间点用T4治疗发展严重周围神经病变的II型糖尿病小鼠。为了研究介导Tbeta 4增强糖尿病小鼠神经血管功能的分子机制，将检测Tbeta 4对Ang/Tie 2表达和PI 3 K/Akt信号通路活化的影响。使用药物抑制剂和SiRNA基因敲除技术，我们将研究Ang/Tie 2和PI 3 K/Akt信号通路对调节T ² 4增强的神经血管功能和轴突生长的因果关系。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潜在机制提供新的见解，并导致开发使用T4的新治疗方法。相关性声明：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。在这个建议中，采用糖尿病动物的临床前研究，我试图开发一种新的治疗周围神经病变使用T 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。在这个提议中，我还阐明了T？4治疗有效的分子机制。这项研究将为转化为1期临床试验提供必要的临床前数据。

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.