Innate Immunogenetics & Human Infections

描述(申请人提供)：尽管早在100多年前就发现了结核杆菌，50多年来一直有有效的药物可用，但控制结核分枝杆菌仍然存在一些艰巨的挑战，包括了解宿主耐药的机制和如何开发更有效的疫苗。先天免疫系统使宿主能够将自身与入侵的微生物区分开来，区分病原体，并引发一连串的炎症。这些功能由Toll样受体(TLRs)和Nod样受体(NLRs)调控，调节细菌杀伤，影响获得性免疫反应的形成和宿主的生存。尽管这些基因家族是病原体免疫反应的关键介质，但常见的TLR或NLR基因多态对人类感染易感性的影响尚不清楚。在过去的10年里，我的研究目标一直是了解影响人类对结核病等感染易感性的遗传和免疫学因素，并利用这些知识设计更有效的疫苗和疗法。这些项目包括人类遗传病例对照研究，该研究检查先天免疫基因的等位基因变异是否与人类感染有关。这些关联研究与机械实验相结合，旨在确定哪些分子和细胞反应受这些变体的调控。这项建议的研究目的是通过分子、细胞和人类遗传模型来了解巨噬细胞和肺天然免疫反应变化的临床意义。我的指导目标是提供一个充满活力的科学环境和资源，以促进临床医生科学家在与遗传学和先天免疫相关的患者导向研究中的职业生涯。目前，有7名受训者在我的实验室工作，每个人都在研究先天免疫多态在感染易感性中的不同方面的作用。我们假设先天免疫基因的常见变种调节对肺部病原体的免疫反应。我们最近发现了调控TLR信号转导的基因TOLLIP的几个多态性，它们与结核分枝杆菌(MTB)的易感性有关。在目标1中，我们将研究这些TOLLIP基因多态性如何调节细胞功能，以应对结核分枝杆菌感染。在目标2中，我们将研究TOLLIP对MTB免疫应答的哪些方面进行调节。这些研究目标将与指导目标相协调，以开发一个可供实验室所有受训者使用的集中式天然免疫生物测定库。尽管早在100多年前就发现了结核杆菌，50多年来一直有有效的药物可用，但控制结核分枝杆菌仍然面临着许多艰巨的挑战，包括了解宿主耐药的机制和如何开发更有效的疫苗。这项建议的研究目的是研究先天免疫基因变异如何调节肺结核的肺部免疫反应。指导的目标是提供一个充满活力的科学环境和资源，以促进临床医生科学家在与遗传学和先天免疫相关的患者导向研究中的职业生涯。

DESCRIPTION (provided by applicant): Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine. The innate immune system enables the host to differentiate self from invading microbes, discriminate among pathogens, and initiate a cascade of inflammation. These functions, which are orchestrated by Toll-like Receptors (TLRs) and Nod-like Receptors (NLRs), regulate bacterial killing and influence formation of the adaptive immune response as well as host survival. Although these gene families are critical mediators of the immune response to pathogens, the influence of common TLR or NLR polymorphisms on susceptibility to infection in humans is poorly understood. Over the past 10 years, my research goals have been to understand the genetic and immunologic factors that influence human susceptibility to infections such as tuberculosis and to use this knowledge to design more effective vaccines and therapies. These projects include human genetic case-control studies which examine whether allelic variants of innate immunity genes are associated with human infections. These association studies are coupled with mechanistic experiments designed to determine which molecular and cellular responses are regulated by these variants. The research aims of this proposal are to understand the clinical significance of variation of macrophage and pulmonary innate immune responses with molecular, cellular, and human genetic models. My mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity. Currently, there are 7 trainees working in my laboratory and each is examining a different aspect of the role of innate immunity polymorphisms in susceptibility to infection. We hypothesize that common variants of innate immunity genes regulate the immune response to pulmonary pathogens. We recently identified several polymorphisms in TOLLIP, a gene which regulates TLR-signaling, that are associated with susceptibility to Mycobacterium tuberculosis (MTb). In Aim 1, we will examine the mechanism of how these TOLLIP polymorphisms regulate cellular function in response to infection with MTb. In Aim 2, we will examine which aspects of the immune response to MTb are regulated by TOLLIP. These research aims will be coordinated with a mentoring aim to develop a centralized innate immunity bioassay bank that can be utilized by all trainees in the laboratory. Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine. The research aims of this proposal are to examine how variation of innate immunity genes regulates the pulmonary immune response to tuberculosis. The mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity.