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

Toll 样受体 1 定位和运输的年龄相关缺陷

• 批准号: 8732599
• 负责人: Alexander Panda
• 金额: $ 14.67万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732599
• 关键词: Advisory Committees; Age; Age-Years; Aging; Appointment; Bacterial Infections; Basic Science; Berlin; Biometry; Biotinylation; Cell membrane; Cells; Cellular biology; Clinical; Clinical Research; Collaborations; Communicable Diseases; Complement; Complex; Confocal Microscopy; Critical Care; Data; Defect; Dendritic Cells; Deterioration; Development; Doctor of Philosophy; Educational Curriculum; Elderly; Environment; Event; Faculty; Fluorescence Resonance Energy Transfer; Gene Expression; Genetic Transcription; Geriatrics; Germany; Goals; Health Policy; Heterodimerization; Host Defense; Human; Immune response; Immune system; Immunity; Immunobiology; Immunology; Impairment; Individual; Informatics; Institution; Internal Medicine; Investigation; Kinetics; Label; Laboratory Research; Leadership; Lung; Measurement; Measures; Mediating; Medicine; Mentors; Mentorship; Metabolic; Molecular Chaperones; Morbidity - disease rate; Myelogenous; Natural Immunity; Older Population; Pathway interactions; Patient Care; Peripheral Blood Mononuclear Cell; Physicians; Physiologic pulse; Population; Positioning Attribute; Predisposition; Production; Proteins; Public Health; Public Health Schools; Publishing; Qualifying; Research; Research Training; Role; Scientist; Supervision; Surface; TLR1 gene; Techniques; Time; Toll-Like Receptor 1; Toll-like receptors; Training; Translational Research; Universities; Vaccine Research; Vaccines; Virus Diseases; Work; age group; age related; arm; base; career; career development; clinical epidemiology; cytokine; functional decline; immune function; immunosenescence; medical schools; monocyte; mortality; novel; peripheral blood; programs; protein expression; receptor function; response; trafficking; young adult

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.

描述（由申请人提供）：候选人：候选人是一名内科，传染病，肺部和重症监护医学培训和委员会认证的医生，目前是耶鲁大学医学院布鲁克代尔领导老年研究员和研究医学项目的博士候选人。他在老年医学和研究方面有着良好的记录。他曾就读于德国柏林的亚历山大·冯·洪堡大学医学院，并在约翰·霍普金斯大学公共卫生学院获得公共卫生硕士学位。他在老龄化领域一直表现出领导才能，从他在老年医学方面的培训开始，早期研究老年人保健政策，最近在基础科学领域致力于老年人疫苗研究。在他的临床培训期间，他开始意识到老年患者护理的复杂挑战。因此，他决定将研究重点放在理解人类免疫反应与年龄相关的变化上，重点是先天免疫。他的长期职业目标是在学术机构获得终身职位，并将大部分时间用于基础科学研究。申请人将在两位高水平导师的指导下，在由免疫学、老年病学、临床流行病学和生物统计学专家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。申请人提出的教学课程和参与研究研讨会的重点计划，将补充他完成的研究生课程。最终，当候选人以终身教职的身份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，从事衰老和肺部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衰老和胡椒中心项目有长期合作，该项目为人类研究提供招聘、信息和生物统计支持，并与位于同一栋楼的耶鲁大学免疫生物学系主任有长期合作关系。研究：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）人群中toll样受体（TLR）功能普遍缺陷。在这里，我们的重点是了解在老年人中观察到的TLR1表面表达与年龄相关的减少的基础，这似乎是由翻译后机制引起的。我们将采用一系列最先进的细胞生物学技术来评估TLR1的动力学和运输中与年龄相关的变化，包括TLR伴侣蛋白（如PRAT4a）的贡献，我们发现PRAT4a在老年人的细胞中表达减少。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。