Impact of AMP-activated kinase on sex differences in hypertrophic cardiomyopathy

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DESCRIPTION (provided by applicant): The candidate, John P. Konhilas, Ph.D., is a newly appointed Assistant Professor with a newly funded R01 that synthesizes his pre- and post-doctoral training by studying the physiological impact brought about by changes in the molecular and biochemical biology of the heart in response to disease and sex. Dr. Konhilas' immediate career goal is to acquire the research and professional skills necessary for achieving his long-term goal of developing an integrative and translational research program to explore the metabolic, molecular and physiologic adaptation of the heart to disease and sex. The proposed K02 research and development plan will provide Dr. Konhilas with the protected time and additional resources to achieve this goal. Career Development Plan: The career development and research plan outlined in this proposal builds upon my R01 and will provide the scientific foundation upon which to guide future research efforts whereby we can more clearly define the mechanism underlying sex dimorphisms in the clinical HCM population. Training activities during the award period include, (1) acquiring new and refining present research skills, (2) structured activities including coursework in scientific integrity, biostatistics, and attendance/presentation at journal clubs, scientific meetings, and mentoring interactions. Environment: The foundation for Dr. Konhilas' newly established his laboratory is built. Dr. Konhilas has also assembled a team of consultants to provide guidance in every facet of the proposal. Research: Sex/gender differences exist in human cardiac disease resulting from many disease etoilogies including hypertension, myocardial infarction, and hypertrophic cardiomyopathy (HCM). The hearts of women with these disorders maintain, at least, adequate cardiac function whereas men typically demonstrate increased chamber dilation and wall thinning, all signs of progressively deteriorating cardiac disease. Humans with HCM caused by an autosomal dominant mutation (R403Q) in the predominant motor protein in the heart (1-myosin heavy chain) show a similar sex difference in cardiac disease progression. Like their human counterparts, male mice expressing the R403Q mutation in the heart develop HCM characterized by progressive left-ventricular dilation and cardiac dysfunction whereas females show hypertrophy without dilation or dysfunction. However, the mechanisms that underlie these differences remain unknown. Because the R403Q mutation resides in the motor protein of the cellular contractile apparatus, hearts expressing the R403Q mutation are energy deprived and that this may be due to the increased energetic cost of contraction when expressing the R403Q mutation. Therefore, the prediction is that the observed sex difference may result from the inability of male hearts to match this increased energetic demand compared to females. In support of this idea, male R403Q hearts show metabolic abnormalities consistent with an energy-deprived state. Adenosine monophosphate-activated kinase (AMPK) may be a central regulator of this sex difference because of its established role in (1) sensing changes in cellular energy state, (2) regulating mediators of energy producing pathways, and, (3) directly modifying contractile proteins by phosphorylation. Yet, no studies have systematically addressed AMPK sex dimorphisms in mice with the R403Q mutation. Therefore, the outlined experimental plan is designed to concisely test the hypothesis that male hearts do not adapt appropriately to the increase in energetic demand caused by the R403Q HCM mutation, which leads to progressively worsening cardiac dysfunction. The hypothesis to be tested is that the key mechanism that underlies this sexual dimorphism is an altered AMPK signaling axis in males compared to females. Moreover, these studies will provide a critical foundation upon which to guide future research into defining fundamental differences in metabolic and oxidative capacities of male and female hearts in order to more completely elucidate sex differences in cardiovascular disease etiology and treatment in the human population. PUBLIC HEALTH RELEVANCE: Males and females respond differently to cardiac disease such that males typically show signs of worsening cardiac function and females do not. The way males and females uniquely handle the energetic deficiencies associated with cardiac disease underlies these differences. Therefore, it is of major clinical significance that the mechanistic link be determined between cardiac disease, sex/gender differences and energetic regulators in the heart. )