AND SUPPLEMENT TO U01 The overall objective of the ?Normal Aging Lung Cell Atlas? (NALCA), our response to RFA-HL-19-012 (Deciphering the Molecular Landscape of Lung Aging in Humans U01), is to generate a compendium of the dynamic cell specific changes in mRNA, microRNA, and epigenetic marks that happen during lung aging with a focus on single cells and the alveolar microenvironment. We plan to use this compendium to generate a dynamic temporal regulatory model of normal human lung aging. To address this objective, we have assembled a multidisciplinary group of experts in lung genomics, epigenomics, bioengineering, aging, alveolar development, systems and computational biology. The premise of this proposal lies in the availability of resources, including normal human lungs at different ages, aged wild-type and aging relevant genetically modified mice, unique expertise in high throughput technologies including single cell RNAseq, laser capture microdissection, methylation profiling, proteomics and tissue engineering, and proven track record in developmental of analytical approaches that dissect temporal regulatory networks. This objective also largely benefits from synergisms with other non-overlapping NIH-NHLBI and NIH-NIA projects headed by the coinvestigators on this proposal. We will address the objectives of this application by the following specific aims:
Aim 1 : To identify cell and microenvironment specific changes in coding and non-coding RNAs across human lung aging.
Aim 2 : To identify key time points in lung aging using detailed temporal analysis of mouse lung aging.
Aim 3 : To develop a comprehensive transcriptional dynamic regulatory multicellular model of lung aging. The completion of these specific aims will lead to the generation of the Normal Lung Aging Cell Atlas ? a resource for the scientific community that will allow both better understanding of normal lung resident cell aging, as well as the role of aging related mechanisms in other chronic lung diseases.
SUPPLEMENT NARRATIVE Quantifying the cell specific sexual dimorphism normal lung aging is outside the parent application. Here, we propose expanding the ?Normal Aging Lung Cell Atlas?, our multi-omic analysis of lung aging, to more specifically focus on the variable of biological sex. Through incorporating analyses that focus on the cell specific impacts of sex in lung aging, we hope to elucidate novel molecular mechanisms governing the sex-specific differences in lung structure, function, aging, and susceptibility to various lung diseases.
