? Combination therapy of insulin-like growth factor (IGF)-I/IGF binding protein (BP)-3 (Iplex, formerly known as Somatokine) is substantially more potent in stimulating skeletal muscle growth than IGF-I therapy alone and prevents its negative side effects, although the mechanisms of IGFBP-3's enhancing effects are not well described. Recent studies suggest that the local production of IGFBP-3 helps mediate IGF-stimulated myoblast differentiation. In fact, IGFBP-3 is produced in differentiating myoblasts, it inhibits myoblast proliferation, localizes to the nucleus and directly binds a subunit of RNA polymerase II (Rpb3) that specifically regulates myoblast differentiation via its interactions with the myogenic transcription factors myogenin and ATF4. IGFBP-3 is also a potent suppressor of some prostate and breast cancers. Thus, its positive effects on skeletal muscle growth may additionally protect against the muscle atrophy and negative nitrogen balance that often occurs in cancer patients while simultaneously stimulating tumor cell apoptosis. A better understanding of IGFBP-3's myogenic role could therefore lead to improved treatments for growth impairments and cancer associated cachexia in addition to muscular dystrophies. The long-term goal of the laboratory is to describe the underlying mechanisms of IGFBP-3-stimulated growth regulation. The immediate goal of these studies is to determine the specific inhibitory mechanisms of IGFBP-3 on myoblast proliferation. The project's specific aims are (1) to determine the structural constraints necessary for IGFBP-3 growth inhibition and (2) to determine whether IGFBP-3 manipulates ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR051917-02
Application #
7393341
Study Section
Special Emphasis Panel (ZAR1-EHB-H (J1))
Program Officer
Nuckolls, Glen H
Project Start
2007-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$73,255
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
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Interlichia, Jillian P; Williams, Nolann G; Rodgers, Buel D (2010) A rapid, valid and inexpensive assay for measuring epiphyseal plates in mouse tibia. Growth Horm IGF Res 20:171-3
Rodgers, Buel D; Interlichia, Jillian P; Garikipati, Dilip K et al. (2009) Myostatin represses physiological hypertrophy of the heart and excitation-contraction coupling. J Physiol 587:4873-86
Rodgers, Buel D; Roalson, Eric H; Thompson, Cullen (2008) Phylogenetic analysis of the insulin-like growth factor binding protein (IGFBP) and IGFBP-related protein gene families. Gen Comp Endocrinol 155:201-7
Rodgers, Buel D (2008) Letter to the Editor: Overexpression of Myostatin2 in zebrafish reduces the expression of dystrophin associated protein complex(DAPC) which leads to muscle dystrophy. J Biomed Sci 15:841;author reply 843-5
Rodgers, Buel D; Garikipati, Dilip K (2008) Clinical, agricultural, and evolutionary biology of myostatin: a comparative review. Endocr Rev 29:513-34
Davis, Lori K; Rodgers, Buel D; Kelley, Kevin M (2008) Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line. Endocrine 33:32-9