# Investigating the role of mitochondria in thoracic aortic aneurysm pathogenesis

> **NIH NIH K23** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $162,000

## Abstract

PROJECT SUMMARY/ABSTRACT
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...

## Key facts

- **NIH application ID:** 9968361
- **Project number:** 5K23HL141667-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Benjamin John Landis
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,000
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968361

## Citation

> US National Institutes of Health, RePORTER application 9968361, Investigating the role of mitochondria in thoracic aortic aneurysm pathogenesis (5K23HL141667-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9968361. Licensed CC0.

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