Innate Immunogenetics & Human Infections

描述（由申请人提供）：尽管结核杆菌在100多年前被发现，并且有效药物的可用性超过50年，但控制结核分枝杆菌仍然存在许多艰巨的挑战，包括了解宿主耐药性的机制以及如何开发更有效的疫苗。先天免疫系统使宿主能够区分自身与入侵的微生物，区分病原体，并引发级联炎症。这些功能由Toll样受体（TLR）和Nod样受体（NLR）协调，调节细菌杀伤并影响适应性免疫应答的形成以及宿主存活。虽然这些基因家族是对病原体的免疫应答的关键介质，但对常见TLR或NLR多态性对人类感染易感性的影响知之甚少。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，研究先天免疫基因的等位基因变体是否与人类感染有关。这些关联研究与旨在确定哪些分子和细胞反应受这些变体调节的机制实验相结合。本研究拟以分子、细胞及人类遗传学模型探讨巨噬细胞及肺部先天免疫反应变异的临床意义。我的指导目标是提供一个充满活力的科学环境与资源，以促进临床科学家在以患者为导向的研究与遗传学和先天免疫的职业生涯。目前，有7名实习生在我的实验室工作，每个人都在研究先天免疫多态性在感染易感性中的作用的不同方面。我们假设先天免疫基因的常见变异调节对肺部病原体的免疫应答。我们最近发现了TOLLIP（一种调节TLR信号传导的基因）中的几种多态性，这些多态性与结核分枝杆菌（MTb）的易感性相关。在目的1中，我们将研究这些TOLLIP多态性如何调节细胞功能，以响应MTb感染的机制。在目标2中，我们将检查TOLLIP调节对MTb的免疫应答的哪些方面。这些研究目标将与指导目标相协调，以开发一个集中的先天免疫生物测定库，供实验室中的所有学员使用。尽管结核杆菌在100多年前就被发现，并且有效药物的可用性超过50年，但控制结核分枝杆菌仍然存在许多艰巨的挑战，包括了解宿主抗性的机制以及如何开发更有效的疫苗。本研究拟探讨先天免疫基因的变异如何调控肺结核免疫反应。指导的目标是提供一个动态的科学环境与资源，以促进临床科学家的职业生涯在以患者为导向的研究与遗传学和先天免疫。

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.