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

• 批准号: 10861567
• 负责人: Grace Ji-eun Shin
• 金额: $ 10.72万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10861567
• 关键词: 3-Dimensional; Affect; Afferent Neurons; Animal Model; Biochemical; Biological Assay; Bortezomib; Cancer Patient; Cell Surface Proteins; Cells; Chemotherapy-induced peripheral neuropathy; Clinic; Clinical Trials; Coculture Techniques; Collaborations; Data Analyses; Development; Disease; Drosophila genus; Engineered skin; Environment; Epidermis; Etiology; Extracellular Matrix; Functional disorder; Funding; Future; Genes; Genetic; Hand; Health; Human; Immune; Immunologics; Inflammatory; Integrins; Intervention; Investigation; Knowledge; Larva; Lead; Link; Macrophage; Maintenance; Maps; Mediating; Membrane; Methodology; Modeling; Molecular; Monitor; Nerve; Neurons; Neuropathy; Nociception; Nociceptors; Paclitaxel; Pain; Pain Research; Parents; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Persons; Phenotype; Physiological; Physiology; Predisposition; Prevention strategy; Proliferating; Proteins; Proteomics; Protocols documentation; Quality of life; RNA analysis; Recycling; Role; Sensory; Signal Pathway; Skin; Stimulus; Study models; Substrate Interaction; Surface; Symptoms; Testing; Therapeutic; Toxic effect; Work; biological adaptation to stress; cell type; chemokine; chemotherapeutic agent; chemotherapy; cytokine; cytotoxicity; direct application; extracellular; foot; genetic approach; human model; immunoregulation; in vivo; induced pluripotent stem cell; innovation; insight; keratinocyte; novel; novel strategies; novel therapeutic intervention; pain sensitivity; pain symptom; painful neuropathy; parent grant; peripheral pain; personalized strategies; preservation; prevent; protective effect; protein function; receptor recycling; response; skin disorder; superresolution microscopy; therapeutic target; tool; trafficking; transcriptome sequencing; transcriptomics; treatment strategy

The current supplemental funding application aims to extend our understanding of chemotherapy- induced peripheral neuropathy (CIPN) based on the parent grant's innovative hypothesis that neuron-skin interactions are central to this pathology. Because CIPN frequently accompanies painful symptoms in patients that start from hands and feet, my parent grant and this application are directly relevant to pain research. The supplemental aims are related to the parent grant as they share, enhance, and supplement the parent grant’s hypothesis, experimental approaches, and developed tools. Conceptually, it supplements and advances the parent grant by exploring how immune modulation and different chemotherapeutic agents influence neuron- keratinocyte interactions and by performing in-depth analyses of RNA-seq proposed in the parent grant. The first supplemental aim seeks to characterize cell-type-specific pathology to better understand neuron-keratinocyte interactions in CIPN. This involves exploring agent-specific and shared mechanisms in two chemotherapeutics, paclitaxel (parent) and bortezomib (supplement), which have a potential to identify shared and unique CIPN mechanisms, contributing to personalized strategies for prevention and treatment. Further, we aim to gain further insight into keratinocyte pathology following chemotherapeutic treatment using additional molecular and biochemical assays, supplement to parent aims. By evaluating proliferation, cytotoxicity, stress response, and cytokine/chemokine changes, we will map out the intrinsic and extrinsic changes in keratinocytes and gain a comprehensive understanding of keratinocyte’s role in CIPN etiology. The supplement aim also seeks to expand our methodological approach to include in-depth data analyses through a collaboration with Dr. Sezin, leveraging her expertise in omics data analysis within the context of skin and immune cells to identify key genes and signaling pathways that mediate altered keratinocyte-neuron interactions in CIPN. The second supplemental aim enhances the parent aim by considering potential immunological influences in CIPN pathology. This aims to elucidate how different immune states alter CIPN susceptibility, specifically focusing on the impact of different macrophage states on pain sensitivity and their effects on neuron-keratinocyte interactions. Furthermore, an in- depth omics data analysis will elucidate how macrophages modulate keratinocyte-neuron interactions in CIPN. By characterizing the global transcriptomic changes in keratinocytes and neurons under the influence of different macrophage states, we will identify potential therapeutic targets for preventing and treating painful CIPN in a more physiologically relevant human model. Overall, we aim to create a comprehensive 'pain-in-a-dish' model for peripheral pain research and to develop an innovative approach for pain phenotyping involving keratinocyte skin cells. We believe this approach will significantly contribute to pain research, extend its applicability to a spectrum of skin inflammatory conditions, lay the groundwork for future collaboration in conducting innovative pain research related to skin diseases, and expand pain research capacity.

目前的补充资金申请旨在扩展我们对化疗的理解- 诱导性周围神经病（CIPN）基于父母资助的创新假设，即神经元皮肤 相互作用是这种病理学的核心，因为 CIPN 经常伴随患者的疼痛症状。 从手和脚开始，我的父母资助和这个应用程序与疼痛研究直接相关。 补充目标与父补助金相关，因为它们共享、增强和补充父补助金的目标 从概念上讲，它补充和推进了假设、实验方法和开发的工具。 通过探索免疫调节和不同化疗药物如何影响神经元来获得家长资助 角质形成细胞相互作用，并通过对母基金中提出的 RNA-seq 进行深入分析。 补充目标旨在表征细胞类型特异性病理学，以更好地了解神经元角质形成细胞 CIPN 中的相互作用涉及探索两种化疗药物中的药物特异性和共享机制， 紫杉醇（母体）和硼替佐米（补充剂），有可能识别共享和独特的 CIPN 机制，有助于制定个性化的预防和治疗策略 此外，我们的目标是进一步获益。 使用额外的分子和化学疗法深入了解化疗后的角质形成细胞病理学 生化测定，对亲本目标的补充通过评估增殖、细胞毒性、应激反应和 细胞因子/趋化因子的变化，我们将绘制出角质形成细胞的内在和外在变化，并获得 该补充的目的还旨在扩大对角质形成细胞在 CIPN 病因学中的作用的全面了解。 我们的方法论包括通过与 Sezin 博士的合作进行深入的数据分析，利用 她在皮肤和免疫细胞背景下的组学数据分析方面的专业知识，以确定关键基因和 第二个补充目标是介导 CIPN 中角质形成细胞-神经元相互作用改变的信号通路。 通过考虑 CIPN 病理学中潜在的免疫影响来增强父母的目标。 阐明不同免疫状态如何改变 CIPN 易感性​​，特别关注不同免疫状态的影响 巨噬细胞状态对疼痛敏感性及其对神经元-角质形成细胞相互作用的影响。 深度组学数据分析将阐明巨噬细胞如何调节 CIPN 中的角质形成细胞-神经元相互作用。 通过表征不同因素影响下角质形成细胞和神经元的整体转录组变化 巨噬细胞表示，我们将确定潜在的治疗靶点，用于预防和治疗疼痛性 CIPN 总的来说，我们的目标是创建一个全面的“盘子里的痛苦”模型。 用于外周疼痛研究并开发涉及角质形成细胞的疼痛表型创新方法 我们相信这种方法将极大地促进疼痛研究，并将其适用性扩展到其他领域。 皮肤炎症性疾病谱，为未来开展创新合作奠定基础 与皮肤病相关的疼痛研究，扩大疼痛研究能力。