Sensory neuron-skin interaction in health and disease

项目总结 我的职业目标是领导一个独立的研究小组，调查该病的病理和解决办法 解决神经性疼痛的疼痛问题。为了实现这一目标，我建议开发和使用小说翻译 使用人和动物的组合研究皮肤层中神经元-基质相互作用的策略 外周感觉神经病模型。我的研究重点是一种常见的外周感觉 化疗引起的神经病，仅在美国就有300多万人受到影响。在化疗期间- 在接受化疗的癌症患者中，高达80%的患者会发生诱发性周围神经病变(CIPN)， 目前还没有有效的预防或治疗策略。考虑到细胞外环境的动态变化 皮肤感觉神经和角质形成细胞也可以作为伤害性感受器的最新理解，它是 对于了解神经元和角质形成细胞的维持和功能以解决神经病理性疼痛至关重要。 因此，我建议测试神经元和表皮相互作用失调的假设。 CIPN的病理进展。根据我最近的工作，确定了整合素在 CIPN，我的建议有三个目标，使用尖端工具和创新的多学科方法。在……里面 目的1、研究果蝇体内神经元-底物相互作用及其调控机制 CIPN模型。我将使用遗传学和先进的显微镜方法来标记、操纵和检测 在CIPN模型中，神经元与底物接触的亚细胞变化与功能变化有关。vbl.使用 整合素作为模型来理解CIPN背后的细胞表面蛋白介导的机制，我将 表征调节神经元-底物接触的表面蛋白表达的内吞调节因子。 在目标2中，我将使用人类诱导多能干细胞(IPSC)技术来鉴定角质形成细胞-伤害性感受 共培养CIPN模型中神经元的相互作用和特定细胞类型的病理。由于物种差异， 感觉神经元，我希望建立一个人类模型来研究感觉神经元和 外在因素对CIPN的病理进展将提供关键的见解。在目标3中，我将建立和 验证3D人类皮肤-神经共培养CIPN模型以研究神经元-基质关系和 整合素介导的保护作用。因为不同亚型的伤害性神经元针对不同的表皮层和 为周围神经病的独特病理做出贡献，3D工程人类皮肤将被整合到 模特。这将使我能够研究特定亚型的病理学，并解析伤害性神经元终末 CIPN中的变性和功能障碍。这项提议将为病理进展和 神经元-底物相互作用的机制，为我未来的研究奠定了坚实的基础。作为我的 主要专长是使用果蝇模型研究神经科学，研究人类神经元和表皮细胞 需要新的皮肤生物学和干细胞生物学方面的培训。拟议的计划将极大地促进我的事业 目的解决患者顽固性神经病理性疼痛问题。

PROJECT SUMMARY My career goal is to lead an independent research group to investigate the pathology and resolution of pain to solve neuropathic pain problems. To achieve this goal, I propose to develop and use novel translational strategies to investigate neuron-substrate interactions in the skin layer using a combination of human and animal models of peripheral sensory neuropathy. My research focuses on a common type of peripheral sensory neuropathy induced by chemotherapy, which affects over 3 million people in the US alone. While chemotherapy- induced peripheral neuropathy (CIPN) develops in up to 80% of cancer patients treated with chemotherapeutics, there are no effective prevention or treatment strategies. Considering the dynamic extracellular environment of cutaneous sensory nerves and recent understanding that keratinocytes can also function as a nociceptor, it is vital to understand the maintenance and function of both neurons and keratinocytes to solve neuropathic pain. Hence, I propose to test the hypothesis that dysregulation of neuron and epidermal interactions underlie pathological progression of CIPN. Building from my recent work that identified protective roles of integrins in CIPN, my proposal has three aims that use cutting-edge tools and innovative multi-disciplinary approaches. In Aim 1, I will investigate neuron-substrate interactions and their regulatory mechanisms in a Drosophila in vivo CIPN model. I will use genetics and advanced microscopy approaches to label, manipulate, and detect subcellular changes in neuron to substrate contacts and link with functional changes in a CIPN model. Using integrins as a model to understand cell surface protein-mediated mechanisms underlying CIPN, I will characterize endocytic regulators that modulate surface protein expression mediating neuron-substrate contacts. In Aim 2, I will use human induced pluripotent stem cell (iPSC) technology to identify keratinocyte-nociceptive neuron interactions and cell-type-specific pathology in a co-culture CIPN model. Given species differences in sensory neurons, I expect that establishing a human model to investigate the impact of sensory neurons and extrinsic factors on pathological progression in CIPN will provide critical insights. In Aim 3, I will establish and validate a 3D human skin-nerve co-culture CIPN model to investigate neuron-substrate relationships and integrin-mediated protection. Because subtypes of nociceptive neurons target different epidermal layers and contribute to distinct pathology in peripheral neuropathy, a 3D engineered human skin will be incorporated in the model. This will allow me to investigate subtype-specific pathology and to resolve nociceptive neuron terminal degeneration and dysfunction in CIPN. This proposal will provide new insights into pathological progression and mechanisms mediated by neuron-substrate interactions and a strong foundation for my future research. As my primary expertise is in neuroscience using Drosophila models, investigating human neurons and epidermal cells requires new training in skin biology and stem cell biology. The proposed plan will significantly facilitate my career goal to solve intractable neuropathic pain problems in patients.