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

• 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
• 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

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.

项目摘要 我的职业目标是获得终身教职，并建立一个使用量化技术的实验室 阐明复合体体内免疫调节的方法。我的工作目标是了解如何 遗传或环境诱导的负性调节因子变异可影响先天免疫的敏感性 细胞对炎症刺激的反应。免疫学和计算机接口的研究有望取得进展 我们对动态信号电路的理解，它将刺激的质量和数量转化为适当的 功能性反应，从而为针对这些通路的治疗策略提供信息。我以前的经验 在评估体内免疫细胞激活、定量信号分析和计算建模方面 这让我处于一个很好的位置，可以在这些领域的交叉点工作。 必须严格控制对微生物刺激的先天免疫感知，以支持强大的保护性炎症 对感染的反应，同时避免在屏障部位的小挑战时发生炎症。门槛为 炎症反应是由MAPK活性的严格控制决定的。虽然它的激活成分 途径已被很好地研究，炎症研究的一个根本挑战是理解 负性调节调节这些信号，以促进细胞内的定量决策。基因组 广泛的研究将MAPK调节的磷酸酶与慢性炎症性疾病联系在一起 呼吸道和胃肠道，以及这些屏障组织中微生物区系组成的变化 与炎症性疾病有关。考虑到治疗靶向的尝试成功与否参差不齐 MAPK在多种此类疾病中的作用，阐明与疾病相关的遗传因素和 微生物区系依赖的MAPK调节刺激可能会为治疗优化提供信息。这样做的目的是 建议阐明支持对微生物诱导信号进行定量控制的调节机制 巨噬细胞的阈值，并确定这些阈值是否在屏障中受到明显调节 纸巾。目标1中提出的研究将采用定量实验和计算相结合的方法。 解决磷酸酶调节在转录和翻译后的作用的建模方法 MAPK激活动力学的比例水平。这些努力将使我们深入了解 关键调控因子的表达或活性，由遗传变异、组织特异性信号或 药理操作，可以调节巨噬细胞对微生物产品的敏感性。这些实验 在目标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，并将讨论微生物区系依赖的刺激在巨噬细胞信号调节中的作用， 稳定状态和对轻微炎症挑战的反应。巨噬细胞信号的调节可能起到 在抑制屏障组织炎症反应中的关键作用，以及我们为阐明调控所做的努力 这一过程的失调将揭示与疾病相关的遗传因素之间的机械联系， 微生物区系的变化，以及炎症性疾病的发展。 在执行上述研究策略的同时，我将与Martin Meier-Schellershiem博士、Michel Tremblay和Yasmine Belkaid来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区系的研究。我现在的导师罗纳德·杰曼博士一直支持我 形成了这些合作，并在几个国际科学会议上突出展示了我的研究 开会。这些机会帮助我树立了自己作为十字路口调查员的声誉 数量生物学、信号和先天免疫向独立性过渡，并形成长期的 同事们对我在这一过渡时期的工作给予支持和外界的评价。我也会征求意见 来自我早期的职业导师Peter Savage博士和Suzanne Gaudet博士，他们最近在 职业生涯转型的过程。通过支持完成拟议的目标和相关的职业 发展机会，这个奖项将帮助我建立必要的基础，为额外的资金 并为我成功地过渡到科学独立。