Regulation of macrophage transcriptional networks by stress pathways in the skin

项目总结/摘要 该提案描述了一个为期五年的指导培训计划，用于医生的职业发展- 科学家研究如何生理应激途径诱导的儿茶酚胺和糖皮质激素调节 皮肤对病原体的免疫力。目前，人们对转录网络是如何被 这些应激分子全面调节人体对皮肤病原体的炎症反应。使用 高通量RNA测序，这项建议将允许调查如何儿茶酚胺-或 糖皮质激素诱导的转录网络与Toll样受体（TLR）诱导的炎症反应相互交叉 途径。将此网络分析应用于麻风病人的皮损，分析其贡献 麻风病的发病机制最后，研究了应激分子对T细胞极化和抗微生物的影响。 回应M。麻风将被确定，因为它是一种皮肤病原体，其控制依赖于 适当的TLR介导的免疫。该项目解决了NIAMS的几个目标，包括如何神经 输入控制皮肤炎症和宿主防御途径的巨噬细胞，以及它们如何调节T 麻风病中的细胞极化和抗菌途径。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应答，并将完成临床住院 培训和博士后奖学金通过星星计划研究轨道在加州大学洛杉矶分校。通过这个 他将开发新的分子技术，包括高通量RNA测序和 理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 还将扩大他的临床翻译技能，因为这个建议有一个大的翻译组成部分，涉及 健康对照组和麻风病人。这些新的技术和技能可以适用于几乎任何皮肤 disorder.这一关键的培训指导阶段将在斯蒂芬·斯梅尔的指导下进行， 博士，免疫反应转录调控领域的专家，和罗伯特·莫德林，医学博士， 翻译皮肤免疫学研究的先驱，他们都培养了许多独立的 investigators.此外，这两个PI是加州大学洛杉矶分校的NIAMS资助的P50研究中心的合作者 翻译皮肤病，并将能够通过现有的合作提供额外的支持。 K 08奖将允许在更大的目标背景下对这项研究进行调查。本研究 将提高炎症转录网络是如何通过生理调节的理解， 应力途径的皮肤，并提供深入了解潜在的治疗皮肤免疫。这 该计划将允许候选人开发开展该研究项目所需的技能和工具， 同时拥有必要的指导和支持，以实现成熟成为一个独立的目标， 调查员

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.