Genetic and physiological comparison of native human sensory neurons and induced pluripotent stem cells differentiated to sensory neurons

天然人类感觉神经元和分化为感觉神经元的诱导多能干细胞的遗传和生理比较

基本信息

批准号：
10573702
负责人：
Steve Davidson
金额：
$ 44.55万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2024-08-31
项目状态：
已结题

项目摘要

Project Summary Sensory neurons in the dorsal root ganglia are the primary source of nociceptive (pain) signaling and are susceptible to genetic and functional alterations as a result of injury or disease, thus resulting in chronic pain. Understanding the mechanisms underlying these alterations and gaining the capability to reverse them is a major objective of pain research, and is expected to produce medical advances that reduce patient suffering. Most of the existing information on these neurons is derived from animal models, which has unfortunately led to few clinical successes. Recently, increased access and use of human dorsal root ganglia as well as sensory neurons derived from human induced pluripotent stem cells have positioned the field to improve mechanistic understanding in human cells and advance translation to human drug discovery. However, research on native human sensory neurons and differentiated sensory neurons from human stem cells have progressed on independent trajectories, and therefore have not been adequately compared, leaving open the likely possibility that differentiated stem cells exhibit differences from native sensory neurons that are critical for understanding injury and disease progression toward chronic pain. This application aims to first produce a map of gene expression comparing native and stem cell-derived sensory neurons from the same donors. The results will show precisely how well stem cell-derived sensory neurons genetically match to their native human sensory neurons counterparts, and therefore these data can be utilized to guide differentiation protocols and improve the validity and interpretability of stem cell-derived sensory neurons. Second, native human sensory neurons and sensory neurons derived from stem cells will be assessed for key functional alterations evoked by chemotherapy-induced neuropathy, a common clinical cause of chronic pain. Here, a functional signaling pathway leading to chronic pain will be sampled in each population of cells to expand knowledge of human neuropathy and determine whether sensory neurons derived from stem cells offer a valid model of neuropathy. This project will uncover the nature of both native and differentiated sensory neurons and significantly advance both models as tools for therapeutic development in chronic pain, neuropathy, and regeneration of the peripheral nervous system.

项目摘要背根神经节中的感觉神经元是伤害感（疼痛）信号的主要来源，是由于受伤或疾病而易受遗传和功能改变，因此导致慢性疼痛。了解这些改变并获得扭转它们的能力的机制是疼痛研究的主要目标，并有望产生减少患者痛苦的医疗进步。这些神经元的大多数现有信息来自动物模型，不幸的是很少有临床成功。最近，人类背根神经节的访问和使用以及感觉源自人类诱导的多能干细胞的神经元已定位在现场以改善机理在人类细胞中的理解并将转化为人类药物发现。但是，对本地的研究人类感觉神经元和从人类干细胞的分化感觉神经元在独立的轨迹，因此尚未得到充分比较，使可能的可能性保持开放分化的干细胞表现出与天然感觉神经元的差异，这对于理解至关重要损伤和疾病向慢性疼痛的进展。该应用程序旨在首先生成基因图比较来自同一供体的天然和干细胞衍生的感觉神经元的表达。结果将精确地显示了干细胞衍生的感觉神经元与其本地人类感觉匹配的程度如何神经元对应物，因此可以利用这些数据来指导分化协议并改善干细胞衍生的感觉神经元的有效性和解释性。第二，本地人类感觉神经元并将评估从干细胞中得出的感觉神经元的感官神经元。化学疗法引起的神经病，这是慢性疼痛的常见临床原因。在这里，功能信号传导导致慢性疼痛的途径将在每个细胞中进行采样，以扩大人类的知识神经病并确定从干细胞衍生的感觉神经元是否提供了有效的神经病模型。该项目将揭示天然和分化的感觉神经元的性质，并显着发展两种模型都是慢性疼痛，神经病和再生的工具周围神经系统。