This proposal for an NRSA Individual Fellowship is motivated by two overarching goals: 1) to provide a rich environment for learning and growth to support the candidate's development into an effective physician- scientist, and 2) to generate a molecular map of aging in the lung by applying a systems biology approach to the analysis of transcriptomic data obtained over the lifespan of the laboratory mouse. The candidate and his mentors have designed a specific training plan that includes a rigorous research component and lays the foundation for a successful career. Aging is a key risk factor for morbidity and mortality related to diseases that affect the lung, however, the biological mechanisms contributing to this are not understood. The candidate will employ a systems biology approach to analyze already generated datasets to identify molecular pathways of aging in the lung. A better understanding of aging in the lung may ultimately lead to the development of novel therapies for lung diseases in older adults. Gene expression profiling using RNA-Seq has been used to generate ?maps? of tissues by depicting tissues and purified constituent cellular populations on a molecular level. Transcriptional profiles from individuals with disease have been compared to those from healthy individuals in an attempt to develop ?signatures? for a given disease. These signatures can be useful for disease diagnosis as well as for identifying targets for therapy. This proposal focuses on the contributions of two abundant cell populations in the lung, alveolar macrophages and alveolar type II cells (AT2), to the transcriptional signatures of aging in the lung. The candidate has preliminary data demonstrating evidence of an aging signature in alveolar macrophages and AT2 cells purified from mice at 18 months compared with 3 months. This signature persists during an influenza A virus infection challenge. The purpose of this proposal is to employ a systems biology approach to analyze transcriptomic data already obtained by investigators in the candidate's laboratory that includes whole lung tissue, alveolar macrophages, and AT2 cells harvested from mice over the lifespan (2 weeks, and 6,12,18 and 24 months of age).
In Specific Aim 1, the candidate will generate a transcriptional map of aging in murine whole lung and purified cellular populations of alveolar macrophages and AT2 cells.
In Specific Aim 2, the candidate will determine whether the transcriptional signature of aging in alveolar macrophages is cell autonomous or is driven by changes in the alveolar local microenvironment. Over the course of this award, the candidate will learn new systems biology approaches to analyzing large time-series genomic datasets and will develop a comprehensive understanding of the age-related changes in the innate immune system of the lung. The skills developed as part of this project will serve as a guide for the analysis of similar genomic data harvested from aging humans with lung disease.
Aging is a key risk factor for morbidity and mortality related to diseases that affect the lung, including lung cancer, chronic obstructive pulmonary disease, lung fibrosis, and lung infections. The mechanisms contributing to the increased susceptibility of older adults to these diseases are unknown. We hope to identify novel mechanisms of aging in the lung that ultimately lead to new therapeutic options for diseases of the lung in older adults.
