Diabetic skin influences on outgrowth of human iPSC-derived sensory axons

项目摘要： 这项提案详细说明了一项新的研究计划，以检查神经元起源的差异效应 2型糖尿病（DM 2）患者神经上的轴突靶向环境， 理解为什么这些神经退化，并与他们的健康相比，可塑性降低 特别是在表皮内。轴突生长的感觉神经元来源于 人类诱导多能干细胞（iPSC）将在皮肤活检的存在下进行研究。 来自对照受试者和患有糖尿病和不同程度的周围神经病变的患者。 我们假设： 1)细胞起源很重要，感觉轴突来源于 患有DM 2和周围神经病变的受试者将生长和再生更多 慢于来自健康对照iPSC的感觉神经元。 2)再生环境也起着重要的作用，也许更多 比神经元起源重要：感觉轴突，不管它们起源如何， 将在来自DM 2受试者的皮肤基质上更缓慢地再生， 与健康对照皮肤基质相比的周围神经病变 科目 了解这些不同的潜在影响对人类轴突的作用 再生将使我们在未来更好地识别相关分子， 糖尿病神经病变的治疗靶点--一种无法进行有意义的临床研究的疾病 超越优化葡萄糖控制的进步。 来源于人类iPSC的感觉神经元有望推进神经功能领域的研究。 小纤维神经病变，包括糖尿病周围神经病变（DPN）。然而，在这方面， 尚未探索iPSC衍生的感觉神经元与表皮的相互作用。 因此，重要的是进行新的实验，如这里提出的那些， 特异性检查iPSC衍生的感觉神经元的轴突，以确定 当它们在模仿人类的活组织检查皮肤上时， 条件 我们正在解决这一知识差距，利用微流体室， 轴突的神经元细胞体，以研究基本的病理生物学的远端感觉 糖尿病患者的轴突。通过这一建议，我们预计发展一个系统， 来源于人类细胞，以询问抑制DPN中轴突可塑性的因子。

Project Summary: This proposal details a new research plan to examine the differential effects of neuronal origin and axonal target environment on nerves from people with diabetes mellitus 2 (DM2) to understand why these nerves degenerate and have reduced plasticity compared to their heathy counterparts, especially within the epidermis. Axon growth of sensory neurons derived from human induced pluripotent stem cells (iPSCs) will be studied in the presence of skin biopsied from control subjects and patients with diabetes and varying degrees of peripheral neuropathy. We hypothesize: 1) That cellular origin matters and that sensory axons derived from iPSCs of subjects with DM2 and peripheral neuropathy will grow and regenerate more slowly than sensory neurons derived from healthy control iPSCs. 2) That the regenerative environment also plays an important role, perhaps more important than neuronal origin: that sensory axons, irrespective of their origin, will regenerate more slowly on a matrix of skin from subjects with DM2 and peripheral neuropathy compared to a matrix of skin from healthy control subjects. Understanding the role of these different potential influences on human axonal regeneration will place us in a better position in the future to identify the molecules involved and therapeutic targets for diabetic neuropathy- a condition that has defied meaningful clinical advances beyond optimizing glucose control. Sensory neurons derived from human iPSCs hold promise for advancing the field of small fiber neuropathy in general, including diabetic peripheral neuropathy (DPN). However, interactions of iPSC-derived sensory neurons with the epidermis have not been explored. Therefore, it is important to perform novel experiments, such as those proposed here, that specifically examine axons of iPSC-derived sensory neurons to determine potential factors that influence their degeneration when they are in milieu, over biopsied skin that mimics human conditions. We are addressing this knowledge gap by utilizing microfluidic chambers that separate axons from neuronal cell bodies in order to study the basic pathobiology of the distal sensory axons of diabetic patients. Through this proposal, we anticipate the development of a system derived from human cells to interrogate factors that inhibit axonal plasticity in DPN.