Sensory neuron-skin interaction in health and disease

健康和疾病中的感觉神经元与皮肤相互作用

基本信息

批准号：
10592005
负责人：
Grace Ji-eun Shin
金额：
$ 12.54万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592005
关键词：
3-Dimensional Acceleration Affect Afferent Neurons Animal Model Biological Assay Biology Cancer Patient Cell Surface Proteins Cells Chemotherapy-induced peripheral neuropathy Clinic Clinical Trials Coculture Techniques Development Disease Drosophila genus Engineered skin Environment Epidermis Extracellular Matrix Foundations Functional disorder Genetic Goals Hand Health Human Human Engineering Integrins Intervention Investigation Knowledge Label Larva Lead Link Maintenance Mediating Membrane Membrane Proteins Microscopy Modeling Molecular Monitor Nerve Neurons Neuropathy Neurosciences Nociception Nociceptors Paclitaxel Pain Pathologic Pathology Pathway interactions Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Persons Phenotype Physiology Prevention strategy Proteins Proteomics Protocols documentation Quality of life Recycling Research Resolution Role Sensory Skin Stimulus Substrate Interaction Surface Symptoms Testing Therapeutic Toxic effect Training Work career cell type chemotherapy chemotherapy induced neuropathy cutaneous sensory nerve extracellular foot genetic approach human model improved in vivo induced pluripotent stem cell induced pluripotent stem cell technology innovation insight interdisciplinary approach keratinocyte novel novel strategies novel therapeutic intervention painful neuropathy preservation protective effect protein expression protein function receptor recycling response sensory neuropathy species difference stem cell biology superresolution microscopy tool trafficking transcriptomics translational approach treatment strategy

项目摘要

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.

项目摘要我的职业目标是领导一个独立的研究小组，以调查解决神经性疼痛问题的疼痛。为了实现这一目标，我建议开发和使用新颖的翻译使用人和动物的组合研究皮肤层中神经元间相互作用的策略周围感觉神经病的模型。我的研究重点是一种常见的外围感觉化学疗法引起的神经病，仅在美国就影响了300万人。而化学疗法 - 诱导的周围神经病（CIPN）在接受化学治疗药物治疗的癌症患者中发育多达80％没有有效的预防或治疗策略。考虑到动态的细胞外环境皮肤的感觉神经和最近的理解角质形成细胞也可以充当伤害感受器，这是了解神经元和角质形成细胞的维持和功能至关重要，以求解神经性疼痛。因此，我建议检验以下假设，即神经元和表皮相互作用的失调是基础的 CIPN的病理进展。从我最近的工作中构建，该工作确定了整合素的保护作用 CIPN，我的建议具有三个使用最先进工具和创新的多学科方法的目标。在 AIM 1，我将研究果蝇在体内的神经元间相互作用及其调节机制 CIPN模型。我将使用遗传学和高级显微镜方法来标记，操纵和检测神经元的亚细胞变化对底物接触，并与CIPN模型中的功能变化联系。使用整合素作为了解CIPN基础的细胞表面蛋白介导的机制的模型，我将表征了调节介导神经元基底接触的表面蛋白表达的内吞调节剂。在AIM 2中，我将使用人类诱导的多能干细胞（IPSC）技术来识别角质形成细胞 - 感染力共培养CIPN模型中的神经元相互作用和细胞类型特异性病理。给定物种差异感觉神经元，我希望建立人类模型来研究感觉神经元和 CIPN病理进展的外部因素将提供关键的见解。在AIM 3中，我将建立并验证3D人类皮肤 - 神经培养CIPN模型，以研究神经元间的关系和整合素介导的保护。因为伤害性神经元的亚型靶向不同的表皮层和有助于周围神经病的独特病理学，将纳入3D工程的人体皮肤模型。这将使我能够研究亚型特异性病理并解决伤害性神经元终端 CIPN的变性和功能障碍。该建议将为病理发展和由神经元基层相互作用介导的机制，也是我未来研究的强大基础。作为我的主要的专业知识是使用果蝇模型，研究人神经元和表皮细胞的神经科学专业知识需要在皮肤生物学和干细胞生物学方面进行新的培训。拟议的计划将大大促进我的职业生涯解决患者中棘手的神经性疼痛问题的目标。