Age associated defects in localization and trafficking of Toll-like receptor 1

描述（由申请人提供）：候选人：该候选人是一名内科医生，传染病和肺部和重症监护医学的培训和董事会认证，目前是布鲁克代尔老年研究员和博士领导。耶鲁大学医学院研究医学项目的候选人。他在老年医学和研究方面有着良好的记录。他就读于德国柏林的亚历山大冯洪堡大学医学院，并获得约翰霍普金斯公共卫生学院公共卫生硕士学位。他一直在老龄化领域表现出领导才能，从他在老年医学方面的培训开始，早期对老年人医疗保健政策的研究，到最近致力于老年人疫苗研究的基础科学竞技场。在临床培训期间，他意识到老年患者护理面临的复杂挑战。因此，他决定将研究重点放在了解与年龄相关的人类免疫反应变化上，重点是先天免疫。他的长期职业目标是在一家学术机构获得终身职位，大部分时间致力于基础科学研究。申请人将通过在两名高素质导师的监督下，并在由免疫学、老年医学、临床流行病学和生物统计学领导人组成的导师咨询委员会的指导下，实施拟议的研究计划来实现这一目标。申请人提出了教学课程的重点计划，并参加研究研讨会，这将补充他完成的研究生课程。最终，当候选人在终身教职中建立自己的独立研究实验室时，他将整合他的临床和研究培训，以进行肺部衰老和先天免疫反应的转化研究。环境：耶鲁大学的环境非常适合从事人类转化研究。候选人和他的导师与耶鲁大学的老龄化和胡椒中心项目有着长期的合作，该项目为人类研究提供招募，信息学和生物统计学支持，并与耶鲁大学免疫生物学系的领导人有着长期的关系，他们位于同一栋大楼。研究：该候选人最近发表的工作表明，与年轻人（21-30岁）相比，老年人（65岁以上）树突状细胞（DC）群体中Toll样受体（TLR）功能存在普遍缺陷。在这里，我们专注于理解的基础上观察到在老年人，这似乎是从翻译后机制的TLR 1表面表达的年龄相关的减少。我们将采用一系列最先进的细胞生物学技术来评估TLR 1动力学和运输中与年龄相关的变化，包括TLR伴侣蛋白如PRAT 4a的贡献，我们发现其表达在老年人的细胞中减少。总的来说，拟议的研究、职业发展和指导活动将促进候选人作为一名富有成效的医生-科学家的培训。 公共卫生相关性：衰老与免疫功能的进行性下降（免疫衰老）有关，导致对病毒和细菌感染的易感性增加，对疫苗的反应降低。虽然合并症可能导致观察到的死亡率增加，但很明显，与衰老相关的宿主防御功能受损也导致发病率和死亡率增加。我们的研究重点是老年人先天免疫臂的缺陷，我们希望，最终，我们的工作将有助于解释老年人免疫力的下降，并有助于合理开发专门针对老年人的新型治疗和疫苗。

DESCRIPTION (provided by applicant): Candidate: The candidate is a physician trained and board certified in Internal Medicine, Infectious Diseases and Pulmonary and Critical Care Medicine who is currently a Brookdale Leadership in Aging Fellow and Ph.D. candidate in the Investigative Medicine Program at the Yale School of Medicine. He has a track record in geriatric medicine and research. He attended medical school at the Alexander von Humboldt University in Berlin, Germany and earned a Masters in Public Health from the Johns Hopkins School of Public Health. He has persistently shown leadership qualities in the field of aging, starting with his training in geriatric medicine, early research on health care policies for the elderly and more recently in the basic science arena dedicated to vaccine research for the elderly. During his clinical training, he became aware of the complex challenges in the care of patients in the geriatric age group. As a result, he decided to focus his research on understanding age associated changes in human immune responses, with an emphasis on innate immunity. His long-term career goal is to obtain a tenure-track position at an academic institution with a majority of his time dedicated to basic scientific investigation. The applicant ill achieve this objective by carrying out the proposed research plan under the supervision of two highly qualified mentors, and with guidance by a Mentorship Advisory Committee composed of leaders in immunology, geriatrics, and clinical epidemiology and biostatistics. The applicant proposes a focused program of didactic courses and participation in research seminars that will complement his completed graduate curriculum. Ultimately, when the candidate establishes his own independent research laboratory in a tenure-track faculty appointment, he will integrate his clinical and research training to pursue translational research on aging and innate immune responses in the lung. Environment: The environment at Yale is ideal for pursuing human translational research. The candidate and his mentors have a longstanding collaboration with the Program on Aging and Pepper Center at Yale, which provide recruitment, informatics and biostatistical support for human studies, and have longstanding relationships with leaders in the Department of Immunobiology at Yale, who are located in the same building. Research: The candidate's published work recently demonstrated a generalized defect in Toll-like Receptor (TLR) function in dendritic cell (DC) populations from older (over 65 years), compared to young (21-30 years) individuals. Here, we focus on understanding the basis for the age-associated decrease in TLR1 surface expression observed in older individuals, which appears to arise from post-translational mechanisms. We will employ an array of state of the art cell biology techniques to evaluate age-associated changes in the kinetics and trafficking of TLR1 including the contribution of TLR chaperone proteins such as PRAT4a, whose expression we have found to be decreased in cells from older individuals. Taken together, the proposed research, career development and mentoring activities will facilitate the candidate's training as a productive physician-scientist. PUBLIC HEALTH RELEVANCE: Aging is associated with a progressive decline in immune function (immunosenescence) resulting in increased susceptibility to viral and bacterial infections and decreased response to vaccines. While it is likely that comorbid conditions contribute to the observed increase in mortality, it is clear that impaired host defenses associated with aging also contribute to increased morbidity and mortality. Our research focuses on defects of the innate immunity arm in older adults, and we hope that, ultimately, our work will help explain the deterioration of immunity seen in older adults, and aid in the rational development of novel treatments and vaccines geared specifically towards older adults.