Project Summary
In a well-received preprint, 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. 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 will focus on innovative mammalian ex vivo, in vitro, and in vivo models
of age-dependent transcriptome imbalance, and machine-learning approaches. 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 determine whether SFPQ regulates transcriptome imbalance in aging. Aim 2 (K99):
To determine whether adaptive changes in proteostasis buffer transcriptome imbalance during aging after
influenza A pneumonia. Aim 3 (R00): To causally link transcriptome imbalance to the age-related susceptibility
to influenza A 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.