Saturday, November 23, 2024
11/23/2024
Abstract The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the framework that will prepare the applicant for a successful career as a physician scientist. Much of the applicant’s career development will come from work in electronic cigarette (eCig) inhalation-induced cardiopulmonary dysfunction research, and she will be provided the invaluable opportunity to carry out high quality research using a murine model of chronic intermittent eCig vapor exposure. Cardiopulmonary diseases are the leading causes of death worldwide, and cigarette smoking remains the most significant and preventable risk factor. While cigarette smoking prevalence has steadily declined since 1950, there has been a recent drastic increase in the popularity of eCig or electronic nicotine delivery systems (ENDS). Despite the perception that these products are “safer” alternatives to cigarette smoking, recent cases of eCig or vaping product use-associated lung injury, denoted EVALI, demonstrate a strong potential for harm. The impact of eCig on cardiopulmonary function has yet to be fully elucidated; however, the applicant’s mentoring team demonstrated that chronic nicotine vapor inhalation alone induces activation of the renin-angiotensin system (RAS) and pulmonary hypertension (PH) in mice. Furthermore, preliminary data for this proposal indicate nicotine induces vascular dysfunction. While the previous study demonstrates that nicotine has detrimental cardiopulmonary impacts, it is unknown if the addition of other eCig components (e.g. propylene glycol/vegetable glycerin) will produce the same or greater harmful effects. Thus, investigation into the possible synergistic activity of eCig additives with nicotine is warranted. The OBJECTIVE of this proposal is to evaluate the effects of chronic eCig vapor inhalation on cardiopulmonary function, which could contribute to EVALI, in a murine model of chronic eCig vapor inhalation. The proposed HYPOTHESIS is that chronic eCig vapor inhalation disrupts RAS homeostasis, leading to vascular dysfunction, PH, and right ventricular (RV) remodeling. The proposed study will employ a wide variety of state-of-the-art tools and techniques to test the hypothesis using two specific aims: (1) Chronic eCig vapor inhalation promotes vascular dysfunction, PH, and RV remodeling, and (2) Mechanisms of chronic eCig vapor inhalation-induced cardiopulmonary dysfunction depend on RAS activation and angiotensin signaling mediated by the angiotensin type I receptor (AT1R). In addition, this study will investigate if blocking angiotensin receptor signaling with Losartan will protect against eCig vapor inhalation-induced cardiopulmonary dysfunction. Findings from this study will advance our understanding of the detrimental effects of eCig on the cardiopulmonary system and may identify novel therapeutic targets for the treatment of eCig related cardiovascular and pulmonary diseases (CVPD). With the support of a strong multidisciplinary mentoring team, completion of the proposed training plan will ensure that the applicant is ready to embark on a career in academic medicine.
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