DISSECTING THE IMMUNE BASIS OF DISEASE AND THERAPY

描述(由申请人提供)：人类自身免疫性疾病发病和/或调节的免疫机制代表了人类疾病中一个非常重要但研究严重不足的方面。我们对自身免疫及其内在调控的理解来自于对动物模型的广泛研究，这些动物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调节其无数免疫效果的机械性见解非常有限。为了开发更好的诊断和治疗策略，关键是直接研究人类免疫疾病，并考虑到临床情况的限制，尽可能地剖析免疫治疗的机制。这不仅将提供宝贵的见解，而且将使我们能够开发出更好的这些疾病的模型，纳入疾病未被充分代表的方面。考虑到这一点，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，特别是专注于免疫介导性疾病及其治疗的基础过程。这一K24职业生涯中期研究人员奖将为PI提供资源和受保护的时间，以指导处于该研究领域职业生涯不同阶段的内科科学家。PI实验室的主要重点是多发性硬化症的免疫学，多发性硬化症是一种免疫介导的中枢神经系统脱髓鞘疾病。这里提出的研究将应用当前关于多发性硬化症免疫系统的知识来开发一种诊断实验室测试，用于对这种疾病的免疫监测。为合适的学员提供的其他合作项目包括剖析丙型肝炎病毒感染背后的免疫失调，临床前验证用于最大限度减少移植物抗宿主疾病的治疗同种异体消耗，以及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量的住院医生和研究员计划(包括MD/博士和MD候选人)以及对研究特别感兴趣的初级教员。他是跨多个科室的多个协作团队的积极参与者，并在指导MSTP的学生、住院医生、研究员和病理学、神经病学和内科的初级教员方面有着良好的记录。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，并已建立了多种内部支持机制和基础设施。这一奖项将极大地促进在这一重要的NIAID努力中培训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.