Regulation of macrophage transcriptional networks by stress pathways in the skin

皮肤应激途径对巨噬细胞转录网络的调节

• 批准号: 8750802
• 负责人: PHILIP SCUMPIA
• 金额: $ 13.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750802
• 关键词: Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Affect; Agonist; Award; Biological Assay; Biology; Catecholamines; Chromatin; Clinical; Collaborations; Cutaneous; Data Set; Dendritic Cells; Disease; Doctor of Philosophy; Failure; Fellowship; Funding; Generations; Genes; Glucocorticoids; Goals; High-Throughput RNA Sequencing; Histones; Host Defense; Human; Immune; Immune response; Immunity; Immunology; Immunomodulators; Immunoprecipitation; In Vitro; Inflammatory; Inflammatory Response; Investigation; Lead; Lepromatous Leprosy; Leprosy; Localized Disease; Mediating; Mediator of activation protein; Mentors; Mentorship; Methodology; Mining; Modeling; Molecular; Mus; Mycobacterium leprae; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nature; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phase; Physicians; Physiological; Postdoctoral Fellow; Production; RNA Sequences; Regulation; Research; Research Personnel; Research Project Grants; Residencies; Role; Scientist; Sepsis; Signal Pathway; Signal Transduction; Skin; Specimen; Stress; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; Techniques; Therapeutic; Therapeutic Intervention; Toll-like receptors; Training; Training Programs; Transcriptional Regulation; Translational Research; Tuberculoid leprosy; Work; Wound Healing; adrenergic; antimicrobial; base; biological adaptation to stress; career development; experience; gene induction; improved; inhibitor/antagonist; insight; killings; macrophage; pathogen; programs; promoter; public health relevance; relating to nervous system; response; restriction enzyme; skills; skin disorder; skin lesion; therapeutic target; tool; transcription factor

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year mentored training program for the career development of a physician- scientist to examine how physiologic stress pathways induced by catecholamines and glucocorticoids regulate cutaneous immunity to pathogens. Currently, little is known about how transcriptional networks elicited by these stress molecules globally regulate inflammatory responses to cutaneous pathogens in humans. Using high throughput RNA sequencing, this proposal will allow the investigation of how catecholamine- or glucocorticoid-induced transcriptional networks intersect with Toll-like receptor (TLR)-induced inflammatory pathways. This network analysis will be applied to skin lesions of leprosy patients to analyze their contribution to leprosy pathogenesis. Finally, the effects of stress molecules on T cell polarization and antimicrobial responses to M. leprae will be determined as it is a cutaneous pathogen whose control is dependent on appropriate TLR-mediated immunity. This project addresses several goals of NIAMS including how neural inputs control cutaneous inflammatory and host defense pathways in macrophages, and how they regulate T cell polarization and antimicrobial pathways in leprosy. The candidate previously completed a PhD studying the generation of adaptive immune responses in murine sepsis and will have completed both clinical residency training and a post-doctoral fellowship through the STAR program research track at UCLA. Through this proposal, he will develop new molecular techniques, including high throughput RNA sequencing and the computational analytical skills required to understand transcriptional regulation, restriction enzyme-based promoter accessibility studies, and chromatin histone immunoprecipitation to increase his molecular skills. He will also expand his clinical translational skills, as this proposal has a large translational component involving healthy controls and leprosy patients. These new techniques and skills can be applied to virtually any skin disorder. This critical mentored phase of training will be performed under the mentorship of Stephen Smale, PhD, an expert in the field of transcriptional regulation of immune responses, and Robert Modlin, MD, a pioneer in translational cutaneous immunology research, both of whom have trained numerous independent investigators. Additionally, these two PIs are collaborators on UCLA's NIAMS-funded P50 Center for Research Translation in skin disease, and will be able to provide additional support through their existing collaboration. The K08 award will allow the investigation of this research in the context of a much larger goal. This research will improve the understanding of how inflammatory transcriptional networks are regulated by physiologic stress pathways in the skin and provide insight into potential therapeutics for cutaneous immunity. This program will allow the candidate to develop the skills and tools needed to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator.

项目概要/摘要 该提案描述了一个针对医生职业发展的为期五年的指导培训计划—— 科学家研究儿茶酚胺和糖皮质激素诱导的生理应激途径如何调节 皮肤对病原体的免疫力。目前，人们对转录网络是如何引发的知之甚少。 这些应激分子全局调节人类对皮肤病原体的炎症反应。使用 高通量 RNA 测序，该提案将允许研究儿茶酚胺或 糖皮质激素诱导的转录网络与 Toll 样受体 (TLR) 诱导的炎症相交叉 途径。该网络分析将应用于麻风病患者的皮损，以分析其贡献 对麻风病的发病机制。最后，应激分子对T细胞极化和抗菌的影响 对麻风分枝杆菌的反应将被确定，因为它是一种皮肤病原体，其控制取决于 适当的 TLR 介导的免疫。该项目解决了 NIAMS 的几个目标，包括神经网络如何 输入控制巨噬细胞中的皮肤炎症和宿主防御途径，以及它们如何调节 T 麻风病的细胞极化和抗菌途径。该候选人之前完成了博士学位研究 在小鼠脓毒症中产生适应性免疫反应，并将完成临床住院医师培训 通过加州大学洛杉矶分校的 STAR 项目研究轨道进行培训和博士后奖学金。通过这个 根据提案，他将开发新的分子技术，包括高通量 RNA 测序和 了解转录调控所需的计算分析技能，基于限制性内切酶 启动子可及性研究和染色质组蛋白免疫沉淀以提高他的分子技能。他 还将扩展他的临床转化技能，因为该提案有很大的转化成分，涉及 健康对照者和麻风病患者。这些新技术和技能几乎可以应用于任何皮肤 紊乱。这一关键的指导阶段培训将在 Stephen Smale 的指导下进行， 博士，免疫反应转录调控领域的专家，罗伯特·莫德林医学博士， 转化皮肤免疫学研究的先驱，两人都培养了许多独立的 调查人员。此外，这两位 PI 是加州大学洛杉矶分校 NIAMS 资助的 P50 研究中心的合作者 翻译皮肤病，并将能够通过他们现有的合作提供额外的支持。 K08 奖将允许在更大的目标背景下对这项研究进行调查。这项研究 将增进对炎症转录网络如何受生理调节的理解 皮肤中的应激途径，并提供对皮肤免疫潜在疗法的深入了解。这 计划将允许候选人发展开展该研究项目所需的技能和工具， 同时拥有实现成熟为独立的目标所需的必要指导和支持 研究者。