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.

项目总结： 这项提案详细介绍了一项新的研究计划，以检验神经元起源的不同影响。 和轴突靶环境对2型糖尿病患者神经的影响 理解为什么这些神经退化，与健康相比，可塑性降低 对应物，尤其是在表皮内。神经细胞来源的感觉神经元的轴突生长 人类诱导多能干细胞(IPSCs)将在皮肤活检的情况下进行研究 来自对照组和糖尿病患者以及不同程度的周围神经病变。 我们假设： 1)细胞起源很重要，来自IPSCs的感觉轴突 患有DM2和周围神经病变的患者将生长和再生更多 慢于来自健康对照IPSCs的感觉神经元。 2)再生环境也扮演着重要的角色，或许更重要 比神经元起源更重要的是：感觉神经轴突，无论它们的来源如何， 在DM2和DM2受试者的皮肤基质上再生会更慢 周围神经病与健康对照皮肤基质的比较 研究对象。 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所涉及的分子和 糖尿病神经病变的治疗目标--一种无视临床意义的疾病 超越了优化血糖控制的进展。 人类IPSCs来源的感觉神经元有望推动 小纤维神经病变一般包括糖尿病周围神经病变(DPN)。然而， IPSC来源的感觉神经元与表皮的相互作用还没有被探索过。 因此，重要的是进行新的实验，如这里提出的那些， 专门研究IPSC来源的感觉神经元的轴突，以确定潜在的因素 影响它们在环境中的退化，通过模拟人类的活组织检查皮肤 条件。 我们正在通过利用分离的微流体室来解决这一知识鸿沟 从神经元胞体中提取轴突以研究远端感觉的基本病理生物学 糖尿病患者的轴突。通过这项建议，我们预计将开发一种系统 从人类细胞中提取，以询问抑制DPN轴突可塑性的因素。