Thoracic aortic aneurysm (TAA) is an aortopathy characterized by abnormal enlargement and degeneration of the aorta. TAA can progress without symptoms and predisposes to aortic dissection, causing significant morbidity and mortality. TAA frequently occurs in heritable and congenital disorders such as Marfan syndrome or bicuspid aortic valve (BAV), but variable expressivity and incomplete penetrance complicate major management decisions. Novel prognostic methods are needed in order to improve clinical care, which requires deeper understanding of mechanisms that determine TAA severity. Evidence from mouse and human data suggest that mitochondrial dysfunction is a characteristic feature of TAA, but mitochondrial oxidative metabolism has not been comprehensively studied in patients. My preliminary data identify the gene COQ8B as a candidate genetic modifier of TAA severity. COQ8B encodes a protein that has a key role in oxidative metabolism. Therefore variants in COQ8B may regulate TAA severity through mitochondrial pathways. My long-term objectives are to improve the mechanistic understanding of TAA and to define the genetic modulators of TAA severity in order to improve clinical predictive models and identify novel therapeutic targets.
Aim 1 will determine the clinical and functional impact of genetic variants in COQ8B on TAA development and progression. I will leverage a human biospecimen respository with over 600 participants that I rapidly accrued at Indiana University School of Medicine (IUSM). I will determine the impact of a COQ8B single nucleotide polymorphism (SNP) on TAA severity and aortic tissue pathology. Mechanistic studies will define the SNP's effect in smooth muscle cells cultured from TAA tissue and determine the effect of a rare COQ8B variant by genome editing induced pluripotent stem cells (iPSCs).
Aim 2 will define oxidative metabolism in genetic TAA. I will test the hypothesis that dysregulation of key pathways of mitochondrial oxidative metabolism is prevalent in TAA. Aortic tissues from patients with heritable or BAV-associated TAA will be studied using combined metabolomic and transcriptomic profiling. The novel dataset will be used to define mitochondrial pathways that are dysregulated in TAA and identify additional pathways contributing to TAA. Defining a critical role for mitochondrial metabolism in TAA and delineating genetic modulators creates a unique niche to develop my career as an independent physician scientist and positions me to become a leader in the fields of cardiovascular genetics and aortopathy. My biospecimen repository will continue to grow throughout the planned studies, and our multidisciplinary aortopathy clinic at IUSM will support future studies. IUSM's top 10 NIH funded Pediatrics Department provides an excellent training environment highly supportive of physician scientist development. My mentoring team includes internationally renowned physician scientists with expertise in each aspect of my aims. The training plan in writing, statistics, clinical trials, iPSC disease models, gene editing, and genomic analysis provides a skillset to transition to independence.
Thoracic aortic aneurysm is a prevalent and currently incurable cardiovascular disease associated with significant morbidity and mortality, including the risk of sudden cardiac death. The proposed research seeks to define the gene COQ8B as a novel genetic modulator of thoracic aortic aneurysm severity while investigating a novel line of mechanistic inquiry into the contribution of mitochondrial metabolism using human aortic tissues. The knowledge arising from this research may lead to improved clinical prognostication methods and identification of novel therapeutic targets, which ultimately promise to alleviate the significant burden of this costly and life-threatening disease.
