Quantitative control of macrophage signaling and inflammation thresholds

巨噬细胞信号传导和炎症阈值的定量控制

基本信息

批准号：
9216991
负责人：
Rachel A Gottschalk
金额：
$ 16.2万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-17 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216991
关键词：
Address Award Bacteria Biology Career Mobility Cells Chronic Chronic Disease Chronic Obstructive Airway Disease Collaborations Complex Computer Simulation Data Decision Making Development Disease Environment Environmental Risk Factor Etiology Evaluation Exhibits Experimental Models Exposure to Faculty Foundations Funding Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Gene Expression Profile Genetic Genetic Transcription Genetic Variation Goals Human Immune Immune Cell Activation Immunology Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune System International Kinetics Laboratories Licensing Ligation Link Lung MAP Kinase Gene MAPK14 gene Mediating Mentors Microbe Minor NF-kappa B Natural Immunity Pathology Pathway interactions Pattern recognition receptor Pharmacology Phosphoric Monoester Hydrolases Play Positioning Attribute Process Production Protein phosphatase Psoriasis Receptor Signaling Regulation Research Research Personnel Respiratory System Respiratory Tract Diseases Rheumatoid Arthritis Role Shapes Signal Induction Signal Transduction Site Small Intestines Stimulus System Technical Expertise Testing Therapeutic Tissues Translating Translational Activation Variant Work base career career development clinically relevant cytokine experience experimental study gene induction genome wide association study gut microbiota immunoregulation in vivo inflammatory lung disease insight macrophage meetings microbial microbiota prevent respiratory microbiota response success targeted treatment tenure track therapeutic target treatment optimization

项目摘要

Project Summary My career goals are to obtain a tenure-track faculty position and to establish a laboratory that uses quantitative approaches to elucidate complex in vivo immune regulation. The objective of my work is to understand how genetic or environment-induced variation in negative regulators can influence the sensitivity of innate immune cells to inflammatory stimuli. Research at the interface of immunology and computation promises to advance our understanding of dynamic signaling circuits that translate stimuli quality and quantity into the appropriate functional response, thus informing therapeutic strategies that target these pathways. My previous experience in assessment of in vivo immune cell activation, quantitative signaling analysis, and computational modeling puts me in an excellent position to work at the intersection of these fields. Innate immune sensing of microbial stimuli must be tightly regulated to support robust protective inflammatory responses to infection, while avoiding inflammation upon minor challenges at barrier sites. The threshold for inflammatory responses is dictated by strict control of MAPK activity. While the activating components of this pathway have been well studied, a fundamental challenge in inflammation research is to understand the negative regulation that scales these signals to facilitate quantitative decision-making within cells. Genome wide association studies have linked MAPK-regulating phosphatases with chronic inflammatory diseases of the respiratory and gastrointestinal tracts, and changes in microbiota composition in these barrier tissues are also associated with inflammatory disease. Considering the mixed success of attempts to therapeutically target MAPK in a variety of such diseases, elucidating the influence of disease-associated genetic factors and microbiota-dependent stimuli on MAPK regulation may inform treatment optimization. The objective of this proposal is to illuminate regulatory mechanisms that support quantitative control of microbe-induced signaling thresholds in macrophages and to determine whether these thresholds are distinctly regulated in barrier tissues. The studies proposed in Aim 1 will use a combination of quantitative experimental and computational modeling approaches to address the role of phosphatase regulation at the transcriptional and post-translational levels on scaling of MAPK activation dynamics. These efforts will yield insight into how changes in the expression or activity of key regulators, resulting from genetic variation, tissue-specific signals, or pharmacological manipulation, can tune macrophage sensitivity to microbial products. The experiments proposed in Aim 2 will interrogate distinct signaling tuning in barrier tissues, specifically the small intestine and lung, and will address the role of microbiota-dependent stimuli in regulation of macrophage signaling, both in the steady state and in response to minor inflammatory challenge. Tuning of macrophage signaling may play a critical role in dampening inflammatory responses in barrier tissues, and thus our efforts to elucidate regulation and dysregulation of this process will inform mechanistic links between disease-associated genetic factors, changes in the microbiota, and inflammatory disease development. While pursuing the research strategy described above, I will work with Drs. Martin Meier-Schellershiem, Michel Tremblay, and Yasmine Belkaid to gain technical skills and enhance my expertise in computational modeling, protein phosphatases, and study of the microbiota. My current mentor, Dr. Ronald Germain, has supported me in forming these collaborations and in presenting my research prominently at several international scientific meetings. These opportunities have helped me to establish my reputation as an investigator at the intersection of quantitative biology, signaling, and innate immunity transitioning to independence, and to form long-term colleagues to provide support and outside evaluation of my work during this transition. I will also seek advice from my early career mentors Drs. Peter Savage and Suzanne Gaudet, who have recently navigated the process of career transition. By supporting the completion of the proposed aims and the associated career development opportunities, this award will help me to establish the necessary foundation for additional funding and for my successful transition to scientific independence.

项目概要我的职业目标是获得终身教职并建立一个使用定量技术的实验室阐明复杂的体内免疫调节的方法。我工作的目标是了解如何遗传或环境引起的负调节因子变异可以影响先天免疫的敏感性细胞对炎症刺激。免疫学和计算接口的研究有望取得进展我们对动态信号电路的理解，将刺激的质量和数量转化为适当的信号功能反应，从而为针对这些途径的治疗策略提供信息。我之前的经历用于评估体内免疫细胞激活、定量信号分析和计算模型让我处于在这些领域交叉领域工作的绝佳位置。必须严格调节微生物刺激的先天免疫感应，以支持强大的保护性炎症对感染的反应，同时避免屏障部位的轻微挑战引起炎症。阈值为炎症反应是由 MAPK 活性的严格控制决定的。虽然这种活性成分途径已得到充分研究，炎症研究的一个基本挑战是了解负调节可缩放这些信号以促进细胞内的定量决策。基因组广泛关联研究已将 MAPK 调节磷酸酶与慢性炎症性疾病联系起来呼吸道和胃肠道，以及这些屏障组织中微生物群组成的变化与炎症性疾病有关。考虑到治疗目标的尝试取得了不同程度的成功 MAPK在多种此类疾病中的作用，阐明了疾病相关遗传因素的影响和 MAPK 调节的微生物群依赖性刺激可能有助于优化治疗。此举的目的提案旨在阐明支持微生物诱导信号定量控制的调控机制巨噬细胞中的阈值并确定这些阈值是否在屏障中受到明显调节组织。目标 1 中提出的研究将结合定量实验和计算解决磷酸酶调节在转录和翻译后的作用的建模方法 MAPK 激活动态缩放的水平。这些努力将深入了解关键调节因子的表达或活性，由遗传变异、组织特异性信号或药理学操作，可以调节巨噬细胞对微生物产物的敏感性。实验目标 2 中提出的将询问屏障组织中不同的信号调节，特别是小肠和肺，并将探讨微生物群依赖性刺激在巨噬细胞信号传导调节中的作用，无论是在稳定状态并响应轻微的炎症挑战。巨噬细胞信号传导的调节可能发挥作用在抑制屏障组织炎症反应中发挥关键作用，因此我们努力阐明调节这一过程的失调将揭示疾病相关遗传因素之间的机制联系，微生物群的变化和炎症性疾病的发展。在追求上述研究策略的同时，我将与博士一起工作。马丁·迈尔-谢勒施姆，米歇尔 Tremblay 和 Yasmine Belkaid 获得技术技能并增强我在计算建模方面的专业知识，蛋白质磷酸酶和微生物群的研究。我现在的导师 Ronald Germain 博士一直支持我在形成这些合作以及在几个国际科学会议上突出展示我的研究会议。这些机会帮助我建立了作为十字路口调查员的声誉定量生物学、信号传导和先天免疫向独立过渡，并形成长期的在此过渡期间，同事们为我的工作提供支持和外部评价。我也会寻求建议来自我早期职业生涯的导师 Drs。彼得·萨维奇 (Peter Savage) 和苏珊娜·高德 (Suzanne Gaudet) 最近在职业转变的过程。通过支持完成拟议的目标和相关的职业发展机会，该奖项将帮助我为额外资金奠定必要的基础以及我成功过渡到科学独立。