Candidate: The candidate, John P. Konhilas, Ph.D., is a research associate endeavoring to broaden his extensive training in cardiovascular physiology to encompass additional biological systems and timely molecular techniques. Dr. Konhilas1 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 regulation of skeletal muscle characteristics during cardiac disease states and exercise in animals as it relates to human disease. The proposed K01 development plan will provide Dr. Konhilas with the additional experience and training 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. Konhilas has assembled a team of mentors to provide guidance in every facet of the proposal. The sponsor, Dr. Leslie Leinwand, is a well-established extramurally funded scientist and a proven mentor. She has provided a productive and nurturing research environment necessary for career development. Research: The hypothesis to be tested states that the oxidative capacity of skeletal muscle is reduced during cardiac disease states and can be recovered by exercise training. To examine the role of critical metabolic mediators in this process, lipoprotein lipase or peroxisome proliferator-activated receptor alpha will be genetically disrupted in skeletal muscle by systemic administration of adeno-associated viral (AAV) vectors at specific times during cardiac disease progression and exercise. In all animals, the skeletal muscles will be analyzed for MyHC content, muscle fiber size, and oxidative capacity. Relevance: Severe skeletal muscle weakness and fatigue upon exertion are major clinical features that occur in patients with congestive heart failure (CHF). The exercise intolerance can be reversed in CHF patients with aerobic exercise independent of central cardiac effects. Therefore, it is of major clinical significance that the mechanistic link be determined between cardiac disease, the associated abnormalities in skeletal muscle, and exercise. This proposal will examine specific regulators of this disease process and evaluate their role during disease and exercise recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR052840-05
Application #
7589768
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Boyce, Amanda T
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$120,096
Indirect Cost
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Birch, Camille L; Behunin, Samantha M; Lopez-Pier, Marissa A et al. (2016) Sex dimorphisms of crossbridge cycling kinetics in transgenic hypertrophic cardiomyopathy mice. Am J Physiol Heart Circ Physiol 311:H125-36
Lipovka, Yulia; Konhilas, John P (2016) The complex nature of oestrogen signalling in breast cancer: enemy or ally? Biosci Rep 36:
Behunin, Samantha M; Lopez-Pier, Marissa A; Mayfield, Rachel M et al. (2016) Liver Kinase B1 complex acts as a novel modifier of myofilament function and localizes to the Z-disk in cardiac myocytes. Arch Biochem Biophys 601:32-41
Lipovka, Yulia; Konhilas, John P (2015) AMP-Activated Protein Kinase Signalling in Cancer and Cardiac Hypertrophy. Cardiovasc Pharm Open Access 4:
Konhilas, John P; Chen, Hao; Luczak, Elizabeth et al. (2015) Diet and sex modify exercise and cardiac adaptation in the mouse. Am J Physiol Heart Circ Physiol 308:H135-45
Behunin, Samantha M; Lopez-Pier, Marissa A; Birch, Camille L et al. (2015) LKB1/Mo25/STRAD uniquely impacts sarcomeric contractile function and posttranslational modification. Biophys J 108:1484-94
Lipovka, Yulia; Chen, Hao; Vagner, Josef et al. (2015) Oestrogen receptors interact with the α-catalytic subunit of AMP-activated protein kinase. Biosci Rep 35:
Chen, Hao; Perez, Jessica N; Constantopoulos, Eleni et al. (2014) A method to study the impact of chemically-induced ovarian failure on exercise capacity and cardiac adaptation in mice. J Vis Exp :
Chen, Hao; Hwang, Hyosook; McKee, Laurel A K et al. (2013) Temporal and morphological impact of pressure overload in transgenic FHC mice. Front Physiol 4:205
Perez, Jessica N; Chen, Hao; Regan, Jessica A et al. (2013) Effects of chemically induced ovarian failure on voluntary wheel-running exercise and cardiac adaptation in mice. Comp Med 63:233-43

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