Estrogenic Effects on Aged Muscle

描述（由申请人提供）：该候选人的近期职业目标是加快她最近获得的R01 （AG AG031743）的研究。本研究的重点是衰老和雌二醇对骨骼肌和肌球蛋白功能的相互作用。该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，并利用这些知识设计最佳策略来预防、逆转或至少减缓随年龄增长而发生的肌肉无力的进展。K02奖将有助于实现这些目标，因为候选人可以减轻许多教学和服务相关的教师责任，从而使她能够集中精力进行研究。为候选人成功实现这些目标的环境是特殊的。老年研究中心、肌肉萎缩中心和鲍威尔妇女健康中心的资深知名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“新研究者”正在建立她的研究团队，K02奖提供的救济时间将用于加强她对实验室博士后研究员和研究生和本科生的培训，扩大现有和建立新的合作，并提交额外的资助申请。本次颁奖期间进行的研究的总体目标是确定导致老年女性肌肉力量丧失的激素介导机制。除了衰老外，女性的力量损失可能与卵巢激素的变化有关，但这些激素对骨骼肌的机制影响尚未阐明。因此，该研究的第一个目的是确定雌二醇治疗在多大程度上改善卵巢功能衰竭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的有益作用不依赖于身体活动。本研究的第三个目的是验证雌二醇对肌球蛋白和肌肉功能的有益作用是由雌激素受体介导的，雌激素受体调节氧化应激相关基因。在本次K02奖结束时，候选人希望她的研究团队成为衰老和激素对肌肉结构和功能影响领域的领导者，并为我们对雌二醇缺乏与年龄相关的肌肉无力的理解做出重大贡献。

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.