I am pleased to present this CDA-2 entitled: Effects of Exercise Training on Blood Microclots, Tissue Oxygenation, and Mitochondrial Health in Veterans with Post-COVID Conditions (PCC). I earned my Ph.D. in Biochemistry at the University of Maryland, Baltimore, where my graduate research focused on developing treatment strategies to bypass mitochondrial bioenergetic dysfunctions commonly associated with neuroinflammation using in vitro cell cultures. While I had limited exposure to clinical research, I developed a strong interest in human studies. Since then, I have worked to build a career in clinical and translational research. My interest in moving to clinical trials was solidified when I was selected for an Advanced Fellowship in Geriatric Research at the Baltimore VA Geriatric Research, Education, and Clinical Center (GRECC) under the mentorship of Dr. Alice Ryan. During my fellowship, I was introduced to many of the aspects of human research and was able to work on adapting my basic science skills for clinical research. This award is the ideal next step for progressing my career goals and developing new skills that will significantly contribute to the quality and strength of future independent research. This proposal will run parallel to Drs. Alice Ryan and Kris Ann Oursler's VA RR&D Merit Award entitled: Home-Based Exercise Tele-Rehabilitation in High-Risk Veterans: Impact of COVID-19 Exposure and Socioeconomic Factor (10/2022-09/2027; I01RX003639) which will be conducted at the Baltimore VA Medical Center. However, this CDA-2 is clearly distinct from the Merit Award and will allow me to leverage the physical, human, intellectual, and financial resources needed to complete this project successfully while focusing on my training goals. The skills and experiences afforded by this award will contribute significantly to my career development by filling in the gaps in knowledge I have pertaining to clinical and translational research and human studies and providing me with an invaluable opportunity to observe and participate in a larger clinical study. PCC affects multiple organ systems, including cardiac, respiratory, neurological, and metabolic. The Veteran population is especially vulnerable to PCC due to a higher prevalence of comorbidities that PCC may exacerbate. Chronic inflammation, blood microclots, and epigenetic changes to DNA methylation patterns have been observed in PCC – all of which have been associated with decreases in mitochondrial health. Exercise training is a well-documented means of reducing chronic inflammation, increasing blood clot fibrinolysis, and modifying DNA methylation patterns. This CDA-2 will examine the effect of PCC on multiple factors associated with mitochondrial health before and after 12 weeks of home-based exercise training in high-risk Veterans who have had a COVID-19 infection with and without PCC. This CDA will test the hypothesis that the benefits of exercise training will improve tissue oxygenation and mitochondrial health by modulating hyperinflammation, reducing the presence of blood microclots through the restoration of fibrinolysis, and inducing beneficial DNA methylation patterns associated with mitochondrial bioenergetics in patients with PCC. The aims of this CDA are to Aim 1: Determine the effects of exercise training on oxygen homeostasis and mitochondrial bioenergetics associated with PCC. Aim 2: Determine the effects of exercise training on blood microclots, DNA methylation patterns, and hyperinflammation associated with PCC. With the mentored research and coursework proposed in this CDA-2, I will 1) gain the knowledge and experience necessary to design, develop, manage, and conduct clinical and translational research as an independent investigator; 2) expand my existing skillset by learning new techniques such as imaging flow cytometry and DNA methylation arrays; and 3) develop computational skills for data analysis of large data sets. My long-term goal is to continue independent research within the VA and pursue research that leverages my background and brings innovative methods to understanding mitochondrial dysfunction and bioenergetic impairment in conditions afflicting Veterans and healthy aging.

Veterans with Post-COVID Conditions (PCC) have a wide array of symptoms such as severe fatigue, muscle weakness, anxiety, and depression, all of which can last for months to years after having COVID-19. PCC may also exacerbate pre-existing medical conditions such as heart disease and diabetes. Earlier studies reported abnormal blood clotting, inflammation, and DNA modifications in PCC patients – abnormalities that may directly affect the body's ability to use oxygen and create energy. Exercise training has many benefits that may reverse these effects by improving blood clot breakdown, reducing inflammation, and promoting beneficial DNA modifications. This Career Development Award (CDA) study aims to determine whether exercise training can improve the metabolic abnormalities seen in high-risk Veterans with PCC.