Characterizing TLR Function of Human Dendritic Cells in the Elderly

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Candidate: The candidate is a physician trained in Internal Medicine and Infectious Diseases who is a fellow in Pulmonary and Critical Care Medicine and a Ph.D. candidate in the Investigative Medicine Program at the Yale University School of Medicine. 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 will achieve this objective by carrying out the proposed research plan under the supervision of two highly qualified mentors (Albert Shaw and Richard Bucala), with guidance by a Mentorship Advisory Committee composed of leaders in immunology (Peter Cresswell and Ruslan Medzhitov), geriatrics (Mary Tinetti), and clinical epidemiology and biostatistics (Heather Allore) at Yale. 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, a decision supported by his mentors. 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, the focus was 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. The PI will employ cell biology techniques including pulse-chase experiments, confocal microscopy and fluorescence resonance energy transfer to evaluate age-associated changes in the kinetics of TLR1 surface expression, intracellular distribution and heterodimerization with TLR2. He will also evaluate the contribution of TLR chaperone proteins such as PRAT4a, the expression of which has been found to be decreased in cells from older individuals. Finally, in anticipation of the candidate's plans for establishing his independent research program, a pilot study of TLR function in lung-derived alveolar macrophages in bronchoalveolar lavage fluid from young and older individuals will be carried out to obtain pilot data. 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, ultimately, we hope that 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.