Alternative Splicing Derived Isoforms in the Cardiac Mitochondria
Description: Cardiac mitochondria produce the bulk of ATP to sustain the energetic needs of the heart. Abnormalities and declines in mitochondrial function are observed in ischemia and reperfusion injuries, cardiac hypertrophy, and aging, and are often accompanied by irregularities of alternative splicing affecting mitochondrial genes. Despite active research, important knowledge gaps remain in the molecular functions of alternative splicing-derived protein isoforms and their role in rewiring the mitochondrial proteome. My Sponsor’s lab has a long-standing interest in applying mass spectrometry and bioinformatics methods toward answering cardiac biology questions. In prior work, our lab combined transcriptomics and proteomics workflows to recover previously hidden alternative isoforms in 19 sub-anatomical regions of the heart, and we discovered distinct expressions of alternative isoforms during stages of iPSC to cardiomyocyte differentiation. More recently, we compared the expression of alternative isoforms between young vs. adult mice and found differential exon usages in genes that code for mitochondrial proteins including in OPA and MFF that are involved in mitochondrial fusion and fission that are documented to deteriorate under aging. Building on these works and my previous training background, I will apply our developed multi-omics workflow and published computational tools to examine the roles of alternative splicing in cardiac mitochondria in aging and development. Specifically, 1) I will define the impact of alternative splicing on mitochondrial proteomes in normal and aging mouse hearts; and 2) I will elucidate the functional roles of alternative protein isoforms in cardiac mitochondria using deep learning algorithms and software tools to predict protein structure and function. I believe the completion of the proposed training and research project will help equip me with the necessary experimental and career skills to achieve my long-term goal of understanding how the dynamic cardiac proteome is regulated to orchestrate complex phenotypes in health and disease.
Funder: American Heart Association
Amount: $161,200
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2025-01-01
End date: 2026-12-31
Investigators: Boomathi Pandi, Boomathi Pandi
Institution: University of Colorado Denver, AMC and DC
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 3
Funder award ID: 25POST1372064
OpenAlex ID: G1865084677