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：
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
项目类别：
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

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

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项目摘要

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.

当前的补充资金应用程序旨在扩展我们对化学疗法的理解 - 基于父授予的创新假设，即神经皮肤的诱导周围神经病（CIPN）相互作用是这种病理学的核心。因为CIPN经常涉及患者的疼痛症状从手和脚开始，我的父母赠款和此应用与疼痛研究直接相关。补充目的与父母分享，增强和补充父母的赠款有关假设，实验方法和开发的工具。从概念上讲，它补充并推进了通过探索免疫调节和不同化学治疗剂如何影响神经元的父母赠款角质形成细胞相互作用，并通过对父母赠款中提出的RNA-seq进行深入分析。第一个补充目的旨在表征细胞型特异性病理学，以更好地了解神经元 - 乳脂细胞 CIPN中的相互作用。这涉及在两种化学治疗学中探索特定特定和共享机制，紫杉醇（父母）和硼替佐米（补充），它们有可能识别共享和独特的CIPN 机制，有助于预防和治疗的个性化策略。此外，我们的目标是进一步获得化学治疗后，使用其他分子和生化测定，补充父母的目标。通过评估增殖，细胞毒性，压力反应和细胞因子/趋化因子的变化，我们将绘制角质形成细胞的内在和外在变化，并获得A 综合了解角质形成细胞在CIPN病因中的作用。补充目标还试图扩展我们通过与Sezin博士的合作进行的方法学方法，包括深入的数据分析她在皮肤和免疫细胞中的OMIC数据分析方面的专业知识，以识别关键基因和介导改变角质形成细胞 - 神经元相互作用的信号通路。第二个补充目标通过考虑CIPN病理中潜在的免疫学影响来增强父母的目标。这是为了阐明不同的免疫状态如何改变CIPN的敏感性，特别关注不同的影响巨噬细胞对疼痛敏感性及其对神经元 - 甲状腺相互作用的影响。此外，深度轨迹数据分析将阐明巨噬细胞如何调节CIPN中角质形成细胞 - 神经元的相互作用。通过表征不同的角质形成细胞和神经元的全局转录组变化在不同的影响下巨噬细胞状态，我们将确定预防和治疗痛苦CIPN的潜在治疗靶标与身体相关的人类模型。总体而言，我们旨在创建一个全面的“痛苦”模型进行周围疼痛研究，并开发一种涉及角质形成细胞的疼痛表型的创新方法皮肤细胞。我们认为，这种方法将极大地有助于疼痛研究，将其适用性扩展到皮肤炎症状况的光谱，为未来进行创新的协作奠定了基础疼痛研究与皮肤疾病有关，并扩大疼痛研究能力。