Candidate: The candidate, Brooke C. Harrison, Ph.D., is a research associate endeavoring to broaden his extensive training in skeletal muscle physiology to encompass additional models of skeletal muscle adaptation and timely molecular techniques. Dr. Harrison's immediate career goal is to acquire the research and professional skills necessary for achieving his long-term goal of developing an independent, extramurally- funded, translational research program focusing on the molecular mechanisms of skeletal muscle adaptation to altered activity in both young and old animals as it relates to the human condition. The proposed K01 development plan will provide Dr. Harrison with the additional training and experience to achieve this goal. Career Development Plan: 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: Dr. Harrison has assembled a team of mentors to provide guidance in every facet of the proposal. The sponsor, Dr. Leinwand, is a well-established extramurally funded scientist and a proven mentor. She will provided a productive and nurturing research environment necessary for career development. Research: Advancing age in humans leads to widespread loss of muscle size, strength, and regenerative potential. These changes have been attributed to the complex interaction of numerous factors including: alterations in circulating growth factors, reduced muscle activation status, and intrinsic alterations within the muscle itself. While small regulatory RNAs called microRNAs have been described as potent modulators of gene expression in a number of biological systems, very little is known about the role of microRNAs in regulating skeletal muscle regeneration following injury or adaptation to altered usage. The working hypotheses to be tested state that microRNAs provide a necessary component of the signaling pathways that direct skeletal muscle regeneration and adaptation to conditions of altered usage, and that these pathways are altered by aging. To test these hypotheses, the expression of 5 candidate microRNAs will be determined in skeletal muscle during regeneration following acute muscle injury and also under conditions of increased and decreased muscular activity, in both young and old mice. MicroRNAs will be over-expressed or inhibited in cells and in mice and the effects of these manipulations on skeletal muscle regeneration following acute injury will be investigated. Finally, the regulatory mechanisms involved in the transcription, processing, and expression of these microRNAs will be investigated.
The loss of muscle mass, strength, and function with advancing age (known as sarcopenia) represents an enormous healthcare burden in the United States. Furthering our understanding of the biology of sarcopenia and associated contributing factors such as decreased muscle activity and chronic disease has wide ranging implications and the potential to save billions of dollars and impact millions of lives.
|Green, Eric M; Wakimoto, Hiroko; Anderson, Robert L et al. (2016) A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 351:617-21|
|Haizlip, K M; Harrison, B C; Leinwand, L A (2015) Sex-based differences in skeletal muscle kinetics and fiber-type composition. Physiology (Bethesda) 30:30-9|
|Guess, Martin G; Barthel, Kristen K B; Harrison, Brooke C et al. (2015) miR-30 family microRNAs regulate myogenic differentiation and provide negative feedback on the microRNA pathway. PLoS One 10:e0118229|
|Ferguson, Bradley S; Harrison, Brooke C; Jeong, Mark Y et al. (2013) Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 110:9806-11|
|Ruas, Jorge L; White, James P; Rao, Rajesh R et al. (2012) A PGC-1? isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151:1319-31|
|Riquelme, Cecilia A; Magida, Jason A; Harrison, Brooke C et al. (2011) Fatty acids identified in the Burmese python promote beneficial cardiac growth. Science 334:528-31|
|Harrison, Brooke C; Allen, David L; Leinwand, Leslie A (2011) IIb or not IIb? Regulation of myosin heavy chain gene expression in mice and men. Skelet Muscle 1:5|