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

糖尿病皮肤影响人类 iPSC 衍生的感觉轴突的生长

• 批准号: 10539034
• 负责人: Mohamed H Farah
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539034
• 关键词: Address; Affect; Afferent Neurons; Axon; Back; Biopsy; Cell Line; Cells; Characteristics; Clinical; Clinical Protocols; Coculture Techniques; Cutaneous; Dermis; Development; Diabetes Mellitus; Diabetic Neuropathies; Distal; Environment; Epidermis; Fiber; Fibroblasts; Future; Growth; Human; Impairment; In Vitro; Intrinsic factor; Knowledge; Microfluidic Microchips; Microfluidics; Modeling; Natural regeneration; Nerve; Nerve Degeneration; Nerve Fibers; Neural Conduction; Neurons; Neuropathy; Patients; Peripheral Nervous System Diseases; Persons; Physiology; Play; Positioning Attribute; Research; Role; Sensory; Severities; Skin; Skin Tissue; System; Tissues; adverse outcome; axon growth; axon regeneration; axonal degeneration; axonal sprouting; biological systems; blood glucose regulation; density; diabetic; diabetic patient; diagnostic tool; experimental study; health difference; in vivo; induced pluripotent stem cell; neuronal cell body; new therapeutic target; novel; regenerative; repaired; therapeutic target; treatment strategy

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.

项目摘要： 该建议详细介绍了一项新的研究计划，以检查神经元起源的差异影响 糖尿病患者2（DM2）的神经的轴突目标环境 了解为什么这些神经退化并与其可塑性相比降低了可塑性 对应物，特别是在表皮中。源自源自的感觉神经元的轴突生长 在皮肤活检的存在下，将研究人类诱导的多能干细胞（IPSC） 来自对照受试者和患有糖尿病的患者以及不同程度的周围神经病。 我们假设： 1）细胞起源很重要，并从IPSC中得出的感觉轴突 患有DM2和周围神经病的受试者将增长和再生 比来自健康对照IPSC的感觉神经元慢。 2）再生环境也起着重要的作用，也许更多 比神经元重要：感官轴突，无论其起源如何 在患有DM2和 与健康对照的皮肤矩阵相比，周围神经病 主题。 了解这些不同潜在影响对人轴突的作用 再生将使我们处于更好的位置，以确定所涉及的分子和 糖尿病神经病的治疗靶标 - 一种违反有意义的临床的疾病 超越优化葡萄糖控制的进步。 源自人IPSC的感官神经元有望推进领域 通常，小纤维神经病，包括糖尿病周围神经病（DPN）。然而， 尚未探索IPSC衍生的感觉神经元与表皮的相互作用。 因此，执行新颖的实验很重要，例如这里提出的实验， 专门检查IPSC衍生的感觉神经元的轴突，以确定潜在因素 影响他们在环境时的变性，而模仿人类的活检皮肤 状况。 我们通过使用分开的微流体室来解决这一知识差距 来自神经元细胞体的轴突为了研究远端感觉的基本病理学 糖尿病患者的轴突。通过这项建议，我们预计系统的发展 源自人类细胞来审问抑制DPN轴突可塑性的因素。