Project Summary
The investigator identified through unbiased analysis of own and published datasets that during aging, and
infection of the lung with influenza A, there is a progressive imbalance in the transcript levels encoded by short
genes relative to those encoded by long genes (revision currently under review in Nature Aging). Failure of gene
expression homeostasis impacts the rheostatic ability of almost all cellular processes implicated in aging
impairing organ function, particularly in response to systemic stress. Transcriptome imbalance could account for
manifestations of aging through several potential mechanisms, including: 1) The dysregulation of individual
genes, 2) A dysregulation of the stoichiometry of macromolecular complexes, 3) A relative upregulation of short
early-response inflammatory genes, 4) A breakdown of the coordination between molecular pathways and
processes encoded by genes of different lengths and 5) A reduction in the capacity of protein homeostasis and
cell stress responses to respond towards external stimuli by sequestering its activity toward a buffering of
transcriptome imbalance. The investigator will test the hypothesis that during aging transcriptome imbalance
globally interferes with the functions encoded by the genome and contributes to the loss of resilience
in older individuals. To address this fundamental question, he suggested mammalian ex vivo, in vitro, and in
vivo models of age-dependent transcriptome imbalance, and machine-learning approaches, but because of
COVID-19 related availability refocused on latter and clinical and multi-omic patient data. Reflecting the
interdisciplinary character, he will work under the supervision of his main mentor Dr. Amaral, a network scientist
and data-scientist, and his co-mentor Dr. Morimoto, a molecular biologist studying protein homeostasis and
aging. Further marking his transition to independence, he will be mentored by Dr. Budinger, an immunologist
studying changes in immune aging, and Dr. McNally, a geneticist and bioinformatician, which is not part of a
project grant of his mentors. Aim 1 (K99): To gain mechanistic insight into the origin of transcriptome imbalance
in aging. Aim 2 (K99): To determine whether adaptive changes in proteostasis buffer transcriptome imbalance
during aging after viral pneumonia. Aim 3 (R00): To causally link transcriptome imbalance to the age-related
susceptibility to viral pneumonia. Importantly, the investigator’s mentoring committee has a very strong track
record of training postdoctoral fellows in transitioning into independent investigators. He will engage in seminars
and learn recent experimental techniques, grant writing, bioethics training, and training on running a laboratory,
and obtain additional off-site training on the biology of aging in mice with the purpose to facilitate collaborations.
Combining the new skills learned during his K99 mentored phase with his prior expertise in data science and
transcriptomics will ensure a strong technical foundation to launch an independent laboratory on gene expression
homeostasis in aging and the mechanisms underlying multi-system dysfunction.