DISSECTING THE IMMUNE BASIS OF DISEASE AND THERAPY

描述（由申请人提供）：作为人类自身免疫性疾病发病机制和/或调控基础的免疫机制是人类疾病中一个非常重要但尚未得到充分研究的方面。我们对自身免疫及其内在调控的理解源于对动物模型的广泛研究，这些模型可能反映也可能不反映人类疾病的基本方面。因此，大多数即将到来的治疗策略也是基于这一知识体系。此外，我们对目前使用的免疫治疗方法如何在人类疾病环境中介导其无数免疫效应的机制见解非常有限。为了制定更好的诊断和治疗策略，考虑到临床情况的限制，直接研究人类免疫疾病并尽可能地剖析免疫疗法的机制至关重要。这不仅将提供宝贵的见解，而且将使我们能够开发更好的这些疾病的模型，包括疾病的代表性不足的方面。带着这样的想法，首席研究员（PI）在以患者为导向的研究中建立了自己的职业生涯，特别关注免疫介导疾病及其治疗的基础过程。这项K24中期职业研究者奖将为PI提供资源和受保护的时间，以指导在该研究领域的不同职业阶段的内科科学家。PI实验室的主要重点是多发性硬化症的免疫学，这是一种免疫介导的中枢神经系统脱髓鞘疾病。本文提出的研究将应用目前关于多发性硬化症免疫系统的知识，为这种疾病的免疫监测开发一种诊断性实验室测试。其他适合学员的合作项目包括剖析丙型肝炎病毒感染的免疫失调，临床前验证治疗性异位消耗以减少移植物抗宿主病，以及血液和免疫疾病的诊断问题。PI自己的部门和部门有大量的住院医师和奖学金项目（包括医学博士/博士和医学博士候选人）以及对研究特别感兴趣的初级教师。他积极参与多个部门的合作团队，并在病理学、神经病学和内科部门指导MSTP的学生、住院医生、研究员和初级教师。德克萨斯大学西南分校的环境为该项目的发展提供了出色的支持，多个内部支持机制和基础设施已经到位。这个奖项将极大地促进在这项重要的NIAID努力中培养下一代科学家的能力。

DESCRIPTION (provided by applicant): The immune mechanisms that underlie the pathogenesis and/or regulation of human autoimmune diseases represent a very important but significantly understudied aspect of human disease. Our understanding of autoimmunity and its intrinsic regulation derives from extensive work in animal models that may or may not reflect essential aspects of the human disease. As a result, most of the upcoming therapeutic strategies are also based on this body of knowledge. Moreover, we have very limited mechanistic insights into how currently used immune therapeutic approaches mediate their myriad immune effects in the human disease setting. To develop better diagnostic and treatment strategies, it is critical to study human immune disease directly and to dissect the mechanisms of immune therapies as best as can be done, given the constraints of the clinical situation. This would not only provide invaluable insights, but would allow us to develop better models of these diseases incorporating under-represented aspects of the disease. With that in the mind, the principal investigator (PI) has built a career in patient-oriented research, specifically focusing on the processes that underlie immune-mediated diseases and their therapies. This K24 mid-career investigator award will provide the PI with the resources and the protected time to mentor physician-scientists at various stages of their careers in this area of research. The major focus of the PI's laboratory is the immunology of multiple sclerosis, an immune-mediated demyelinating disease of the central nervous system. The studies proposed here will apply current knowledge about the MS immune system to develop a diagnostic laboratory test for the immunologic monitoring of this disease. Other collaborative projects available for appropriate trainees include the dissection of immune dysregulation underlying hepatitis C virus infection, the pre-clinical validation of therapeutic allodepletion for minimizing graft-versus-host disease and diagnostic issues in hematologic and immunologic diseases. The PI's own division and department have large residency and fellowship programs (including both MD/PhD and MD candidates) as well as junior faculty with a particular interest in research. He is an active participant in several collaborative teams spanning multiple departments and has a track record of mentoring MSTP students, residents, fellows and junior faculty in the departments of pathology, neurology and internal medicine. The environment at UT Southwestern provides outstanding support for the development of this program, with multiple internal mechanisms of support and infrastructure already in place. This award will greatly facilitate the ability to train the next generation of scientists in this important NIAID endeavor.