Estrogenic Effects on Aged Muscle

描述(由申请人提供)：这位候选人的近期职业目标是加快她最近获得的R01(AG AG031743)正在进行的研究。这项研究集中在衰老和雌二醇对骨骼肌和肌球蛋白功能的交互作用。这位候选人的长期职业目标是阐明与年龄和激素相关的骨骼肌功能丧失的总体机制，并利用这一知识设计出预防、逆转或至少减缓随年龄发生的肌肉无力的最佳策略。这些目标将通过K02奖来促进，因为候选人免除了许多与教学和服务相关的教职职责，从而使她能够集中精力从事研究。候选人成功实现这些目标的环境是特殊的。参与老龄中心、肌肉营养不良中心和鲍威尔妇女健康中心的资深研究人员分别在生物衰老、肌肉和妇女健康问题方面为明尼苏达大学提供了一个卓越的网络。K02奖将使候选人有时间更多地参与由这些中心赞助的活动，这些活动将补充和推进她的研究计划。此外，由于这位“新研究员”正在建设她的研究团队，K02奖提供的缓解时间将被用来加强她可以在她的实验室为博士后研究员和研究生和本科生提供的培训，扩大现有的和建立新的合作，并提交更多的资助申请。本次颁奖期间进行的研究的总体目标是确定荷尔蒙介导的导致老年女性肌肉力量丧失的机制。女性的力量丧失可能与卵巢激素的变化有关，除了年龄的变化，但这些激素对骨骼肌的作用机制尚未阐明。因此，这项研究的第一个目标是确定雌激素治疗在多大程度上改善卵巢功能不全的老年小鼠的肌球蛋白功能和肌肉力量。第二个目的是证明雌二醇对肌球蛋白和肌肉力量是有益的，而不依赖于体力活动。这项研究的第三个目的是验证这样一种假设，即雌激素对肌球蛋白和肌肉功能的有益影响是通过调节氧化应激相关基因的雌激素受体介导的。在K02奖项结束时，候选人希望她的研究团队在衰老和荷尔蒙对肌肉结构和功能的影响方面处于领先地位，并为我们理解与年龄相关的肌肉无力中的雌激素缺乏做出重大贡献。 公共卫生相关性：衰老和雌激素的丧失会导致肌肉无力，从而影响老年人的生活质量。申请者将进行研究，以确定雌激素治疗如何通过改善肌肉力量而使雌激素缺乏的女性受益。

DESCRIPTION (provided by applicant): The immediate career goal of this candidate is to expedite the research being conducted in her recently- awarded R01 (AG AG031743). This research is focused on the interactive effects of aging and estradiol on skeletal muscle and myosin functions. The long-term career goals of this candidate are to elucidate the overall mechanisms underlying age- and hormone-related skeletal muscle functional losses and to utilize this knowledge to devise optimal strategies for preventing, reversing, or at least slowing the progression of muscle weakness that occurs with age. These goals will be facilitated by a K02 award as a result of the candidate being relieved of many teaching and service-related faculty responsibilities, thus allowing her to intensively focus on research. The environment for the candidate to be successful in attaining these goals is exceptional. Senior, well-established investigators involved with the Center on Aging, The Muscular Dystrophy Center, and the Powell Center for Women's Health provide a network of excellence at the University of Minnesota in areas of biological aging, muscle, and women's health issues, respectively. A K02 award will afford the candidate time to become more engaged in activities sponsored by these Centers which will complement and advance her research program. In addition, as this "new investigator" is building her research team, relief time provided by a K02 award will be utilized to enhance the training she can offer to post-doctoral fellows and graduate and undergraduate students in her laboratory, expand current and establish new collaborations, and submit additional grant applications. The overall objective of the research that will be conducted during this award is to determine hormone-mediated mechanisms that contribute to muscle strength loss in aged females. Strength losses in females are likely related to changes in ovarian hormones in addition to aging, but mechanistic effects of these hormones on skeletal muscle have not been elucidated. Thus, the first aim of the research is to determine the extent to which estradiol treatment improves myosin function and muscle strength in ovarian- failed, aged mice. The second aim is to show that estradiol is beneficial to myosin and muscle strength independent of physical activity. The third aim of the research is to test the hypothesis that the beneficial effects of estradiol on myosin and muscle function are mediated by estrogen receptors which regulate oxidative stress-related genes. At the conclusion of this K02 award, the candidate expects to have established her research team as the leader in the area of aging and hormonal effects on muscle structure and function and to have contributed significantly to our understanding of estradiol deficiency in age-related muscle weakness. PUBLIC HEALTH RELEVANCE: Aging and loss of estrogen result in muscle weakness that impacts the quality of life of older adults. The applicant will conduct research to determine how estradiol treatment can benefit estrogen-deficient females by improving muscle strength.