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

描述（由申请人提供）：候选人John P. Konhilas博士，是一位新任命的助理教授，拥有新资助的R 01，通过研究心脏分子和生化生物学变化对疾病和性别的反应所带来的生理影响，综合了他的博士前和博士后培训。Konhilas博士的近期职业目标是获得必要的研究和专业技能，以实现他的长期目标，即开发综合和转化研究计划，探索心脏对疾病和性别的代谢，分子和生理适应。拟议的K 02研发计划将为Konhilas博士提供受保护的时间和额外的资源来实现这一目标。职业发展计划：本提案中概述的职业发展和研究计划建立在我的R 01基础上，将为指导未来的研究工作提供科学基础，从而我们可以更清楚地定义临床HCM人群中性别二态性的机制。在奖励期间的培训活动包括，（1）获得新的和完善目前的研究技能，（2）结构化的活动，包括科学完整性，生物统计学课程，并出席/介绍杂志俱乐部，科学会议和指导互动。环境：Konhilas博士新建立的实验室的基础已经建立。Konhilas博士还组建了一个顾问团队，为提案的各个方面提供指导。调研：人类心脏疾病存在性别差异，包括高血压、心肌梗死和肥厚型心肌病（HCM）等许多疾病病因。患有这些疾病的女性的心脏至少保持了足够的心脏功能，而男性通常表现出增加的腔室扩张和壁变薄，所有这些都是心脏病逐渐恶化的迹象。由心脏主要运动蛋白（1-肌球蛋白重链）中的常染色体显性突变（R403 Q）引起的HCM患者在心脏疾病进展中显示出相似的性别差异。与人类相似，在心脏中表达R403 Q突变的雄性小鼠发生HCM，其特征在于进行性左心室扩张和心脏功能障碍，而雌性小鼠显示肥大而没有扩张或功能障碍。然而，这些差异背后的机制仍然未知。由于R403 Q突变存在于细胞收缩器官的马达蛋白中，因此表达R403 Q突变的心脏被剥夺能量，这可能是由于表达R403 Q突变时收缩的能量消耗增加。因此，预测是，观察到的性别差异可能是由于男性的心脏无法匹配这种增加的能量需求相比，女性。为了支持这一观点，男性R403 Q心脏显示出与能量剥夺状态一致的代谢异常。腺苷一磷酸激活激酶（AMPK）可能是这种性别差异的中心调节因子，因为它在以下方面的作用已确立：（1）感知细胞能量状态的变化，（2）调节能量产生途径的介质，以及（3）通过磷酸化直接修饰收缩蛋白。然而，没有研究系统地解决了AMPK性别二态性与R403 Q突变的小鼠。因此，概述的实验计划旨在简明地测试以下假设：男性心脏不能适当地适应由R403 Q HCM突变引起的能量需求增加，这导致心脏功能障碍逐渐恶化。有待检验的假设是，这种两性异形的关键机制是与雌性相比，雄性中AMPK信号轴的改变。此外，这些研究将提供一个重要的基础，指导未来的研究，以确定男性和女性心脏代谢和氧化能力的根本差异，以更全面地阐明人类心血管疾病病因和治疗的性别差异。 公共卫生相关性：男性和女性对心脏病的反应不同，男性通常表现出心脏功能恶化的迹象，而女性则没有。男性和女性处理与心脏病相关的能量缺乏的独特方式是这些差异的基础。因此，确定心脏疾病、性别/性别差异和心脏能量调节因子之间的机制联系具有重要的临床意义。)

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. )