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ROLE OF CO-CHAPERONE, BAG3, IN MUSCLE DEGENERATION UNDER PHYSIOLOGICAL STRESS

Award Number: R01AR052925
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/27/2010
PERIOD OF PERFORMANCE END DATE: 09/30/2011

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ROLE OF CO-CHAPERONE, BAG3, IN MUSCLE DEGENERATION UNDER PHYSIOLOGICAL STRESS - DESCRIPTION (provided by applicant): Project Summary. BAG3 is a member of co-chaperones that binds to and regulates Hsp70-family molecular chaperones. BAG3 is expressed in muscle and has been reported to possess anti-apoptotic. Mice with homozygous disruption of their bagS genes have been generated, revealing a striking post-natal phenotype whereby animals stop growing after 2 weeks of age, and uniformly die by 4 weeks. These bag3-deficient animals develop myofibrillar degeneration with apoptotic feature. The muscle degeneration is especially severe in the diaphragm and soleus muscles, suggesting that physiological use predisposes to muscle degeneration in the absence of BAG3. In bag3 deficient muscle, accumulation of ubiquitinated protein, upregulation of proteasome subunit and degradation of troponin T has been observed. Ring finger type ubiquitin ligase, Siah family protein directly interact to BAG3 protein. Additionally, several lines of evidence indicate that bagS inhibits the ubiquitin proteasome system. Gene knockdown of bag3 in C2C12 myoblast indicates increased apoptosis and accumulation of ubiquitinated proteins. Taken together, BAG3 appears to be critical for protection of muscle through inhibition of apoptosis and ubiquitin proteasome proteolysis. Experiments are proposed to explore the molecular mechanism of inhibition of apoptosis and ubiquitin proteasome including: (1) Studying the molecular mechanisms of apoptosis caused by bagS-deficiency; (2) To determine the function of BAG3 in regulation of ubiquitin proteasome and interacting protein in skeletal muscle and (3) Generation and Analyzing the effects of bag3 depletion in skeletal muscle by Cre-lox system or skeletal muscle specific over-expression of bag3 in vivo using pathophysiological model and cross mating experiments. Relevance: These studies will provide insights about the roles of BAG3 in muscle cell survival under physiological stress, and may provide us clues for understanding molecular mechanisms of myofibrillar degeneration and for investigating the new target for therapy of muscular degenerative human diseases


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2010 ( Subtotal = $392,874 )
2010	2010	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	001	5	5/26/2010	SUPPLEMENT FOR EXPANSION	$11,774
2010	2010	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/22/2010	NON-COMPETING CONTINUATION	$381,100
														Subtotal = $392,874

Issue Date FY: 2009 ( Subtotal = $384,949 )
2009	2009	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/30/2009	NON-COMPETING CONTINUATION	$377,364
2009	2009	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	7/22/2009	NON-COMPETING CONTINUATION	$7,585
														Subtotal = $384,949

Issue Date FY: 2008 ( Subtotal = $377,364 )
2008	2008	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/29/2008	NON-COMPETING CONTINUATION	$377,364
														Subtotal = $377,364

Issue Date FY: 2007 ( Subtotal = $385,065 )
2007	2007	MEDICAL COLLEGE OF GEORGIA, RESEARCH INSTITUTE	RESEARCH INSTITUTE	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/8/2007	NEW	$0
2007	2007	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/2/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$385,065
														Subtotal = $385,065

Grand Total All Awards = $1,540,252

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ROLE OF CO-CHAPERONE, BAG3, IN MUSCLE DEGENERATION UNDER PHYSIOLOGICAL STRESS

Award Number: R01AR052925

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/27/2010

PERIOD OF PERFORMANCE END DATE: 09/30/2011

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