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

应聘者描述(由申请者提供)：应聘者是一名内科医学、传染病、肺部和危重护理医学方面的训练有素并获得董事会认证的医生，目前是布鲁克代尔老年学领袖研究员和耶鲁医学院研究医学计划的博士候选人。他在老年医学和研究方面有过往记录。他就读于德国柏林亚历山大·冯·洪堡大学医学院，并从约翰霍普金斯大学公共卫生学院获得公共卫生硕士学位。他在老龄化领域坚持不懈地展示了领导才能，从他在老年医学方面的培训开始，对老年人医疗保健政策的早期研究，以及最近在致力于老年人疫苗研究的基础科学领域。在他的临床培训期间，他意识到了老年患者护理方面的复杂挑战。因此，他决定将他的研究重点放在了解与年龄相关的人类免疫反应的变化上，重点放在天然免疫上。他的长期职业目标是在一家学术机构获得终身教职，他的大部分时间都致力于基础科学研究。申请人将在两名高素质导师的监督下，在由免疫学、老年病学、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，以实现这一目标。申请者提出了一个有重点的教学课程和参加研究研讨会的计划，这些课程将补充他完成的研究生课程。最终，当候选人以终身教职的方式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，以从事关于肺部衰老和先天免疫反应的转化性研究。环境：耶鲁大学的环境非常适合从事人类翻译研究。这位候选人和他的导师与耶鲁大学老龄化和胡椒中心项目有着长期的合作关系，该项目为人类研究提供招聘、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保持着长期的合作关系，后者位于同一栋建筑内。研究：这位候选人最近发表的研究表明，与年轻人(21-30岁)相比，年龄较大(65岁以上)的树突状细胞(DC)群体中的Toll样受体(TLR)功能普遍存在缺陷。在这里，我们重点了解在老年个体中观察到的与年龄相关的TLR1表面表达下降的基础，这似乎是由翻译后机制引起的。我们将使用一系列最先进的细胞生物学技术来评估TLR1动力学和运输的年龄相关变化，包括TLR伴侣蛋白的贡献，如PRAT4a，我们发现其在老年人细胞中的表达减少。综上所述，拟议的研究、职业发展和指导活动将有助于候选人作为一名多产的内科科学家进行培训。

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.