Sex-specific regulation of myofibrillar function in the aging heart

项目摘要 射血分数保留性心力衰竭（HFpEF）是心力衰竭患者中最常见的形式， 65岁。目前的治疗方案不能有效治疗HFpEF;因此， 了解导致这种疾病的细胞机制。重要的是，随着女性年龄的增长， HFpEF的发病率高于男性。目前尚不清楚是什么原因导致女性的风险增加。自从一个标志性的 HFpEF的一个特征是松弛受损，这是阐明为什么女性有更高风险的重要一步。 发展HFpEF是为了了解男性和女性之间放松所不可或缺的因素是如何不同的， 女性以及她们如何随着年龄的增长而变化这项建议旨在阐明放松是如何调节男性 而女性在正常的心脏衰老中处于最基本的心肌细胞功能水平，即肌节。通过 研究肌节、肌原纤维小束的力学参数， 可以界定这些差异，并确定造成差异的机制。 初步研究表明，从女性供体心脏分离的肌原纤维的松弛时间延长 与从20至40岁之间的女性供体的心脏分离的肌原纤维相比， 年龄此外，肌原纤维松弛也存在性别差异。进一步的初步研究还表明， 组蛋白去乙酰化酶8（HDAC 8）可能通过乙酰化肌节而调节肌松 proteins.这项建议将确定在非失败的人肌原纤维乙酰化和松弛的性别差异， 年轻人（20-40岁）和老年人（> 60岁）的心脏（目标1）。由于肌原纤维 在人类中观察到的松弛变化在成人（5个月大）和更大的（20个月大）中重现。 年龄）雄性和雌性小鼠，体外和体内小鼠模型将用于询问肌原纤维的变化 松弛老化和HDAC 8的操纵（目的2）。 确定年龄如何影响男性和女性的肌原纤维松弛将提供有价值的见解， 有助于HFpEF发展的机制。这项提案旨在扩大沃尔夫博士的 研究心脏衰老的研究。沃尔夫博士的总体职业目标是研究肌原纤维的性别差异 整个生命周期的力学和本提案中概述的培训将使她能够发展关键技能， 研究心脏衰老所需的经验。Woulfe博士建立了一个导师团队， 衰老、性别差异以及腺病毒生成的分子生物学和HDAC生物学。在一起，这个团队 独特的合格导师和Woulfe博士制定了一个定制的培训计划，提供 技能和知识，以确保适当的研究设计和做法，在一个新的领域， research.

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure in patients over 65 years of age. Current therapeutic regimens do not effectively treat HFpEF; therefore, it is critical to understand cellular mechanisms that cause this disease. Importantly, as women age, they have a higher risk of developing HFpEF than men. It is not known what leads to this increased risk in females. Since a hallmark feature of HFpEF is impaired relaxation, an important step in elucidating why women are at higher risk of developing HFpEF is to understand how factors that are integral to relaxation differ between males and females and how they change with age. This proposal seeks to elucidate how relaxation is regulated in males and females in normal cardiac aging at the most basic level of cardiomyocyte function, the sarcomere. By studying mechanical parameters of small bundles of sarcomeres, myofibrils, key differences in relaxation can be defined and mechanisms that contribute to differences can be identified. Preliminary studies demonstrate relaxation is prolonged in myofibrils isolated from hearts of female donors over 60 years of age compared to myofibrils isolated from hearts of female donors between 20 and 40 years of age. Additionally, there are also sex-differences in myofibril relaxation. Further preliminary studies also suggest histone deacetylase 8 (HDAC8) may play a role in regulation of relaxation through acetylation of sarcomeric proteins. This proposal will define sex differences in myofibril acetylation and relaxation in non-failing human hearts from young adults (20-40 years of age) and older adults (> 60 years of age) (Aim 1). Since myofibril relaxation changes observed in humans are recapitulated in adult (5 months of age) and older (20 months of age) male and female mice, in vitro and in vivo mouse models will be used to interrogate changes in myofibril relaxation in aging and with manipulation of HDAC8 (Aim 2). Identifying how aging affects myofibril relaxation in males and females will provide valuable insight into mechanisms that contribute to the development of HFpEF. This proposal is designed to expand Dr. Woulfe's research to study cardiac aging. Dr. Woulfe's overall career goal is to study sex-differences in myofibril mechanics across the lifespan and the training outlined in this proposal will allow her to develop key skills and experience necessary to study cardiac aging. Dr. Woulfe has established a mentorship team with expertise in aging, sex differences, and molecular biology of adenovirus generation and HDAC biology. Together, this team of uniquely qualified mentors and Dr. Woulfe have developed a custom training plan tailored to provide the skills and knowledge necessary to ensure appropriate research design and practices in a new area of research.