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/或调节基础的免疫机制代表了人类疾病的一个非常重要但研究不足的方面。我们对自身免疫及其内在调节的理解来自动物模型的广泛研究，这些研究可能反映或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，对于当前使用的免疫治疗方法如何介导其在人类疾病环境中的无数免疫作用，我们的机制见解非常有限。为了开发更好的诊断和治疗策略，鉴于临床情况的限制，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模型，将疾病的代表性不足的方面纳入其中。考虑到这一点，主要研究者（PI）已经建立了以患者为导向的研究生涯，特别关注免疫介导的疾病及其治疗的基础过程。这个K24职业中期研究者奖将为PI提供资源和受保护的时间，以指导该研究领域职业生涯各个阶段的医生科学家。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MS免疫系统的知识来开发用于这种疾病的免疫监测的诊断实验室测试。其他可供适当的学员合作项目包括解剖免疫失调的丙型肝炎病毒感染，临床前验证治疗性同种异体耗竭，以尽量减少移植物抗宿主病和血液学和免疫学疾病的诊断问题。PI自己的部门和部门有大型的住院医师和奖学金计划（包括MD/PhD和MD候选人）以及对研究特别感兴趣的初级教师。他是一个积极的参与者，在几个合作团队跨越多个部门，并有指导MSTP学生，居民，研究员和初级教师在病理学，神经病学和内科部门的跟踪记录。UT西南的环境为该计划的发展提供了出色的支持，已经建立了多种内部支持机制和基础设施。该奖项将极大地促进培养下一代科学家在这一重要的NIAID奋进的能力。

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.