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MOLECULAR PHYSIOLOGY OF RESPIRATORY MUSCLES

Award Number: R01HL064641
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2000
PERIOD OF PERFORMANCE END DATE: 02/28/2011

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MOLECULAR PHYSIOLOGY OF RESPIRATORY MUSCLES - Our recent studies have identified a therapeutic approach, based on inhibition of apoptosis, that significantly ameliorates disease in mice that are models for the most common type of human congenital muscular dystrophy (CMD Type IA, due to mutation in the gene encoding Iaminin-a2). Specifically,we found that either inactivation of Bax (a pro-apoptosis protein) or muscle-specific overexpression of Bcl-2 (an anti-apoptosis protein) produced a several-fold increase in lifespan and increased the growth rates and muscle functions of Iaminin-a2-null mice. Our work thus provides proof-of-conceptthat anti-apoptosis therapy is of potential therapeutic benefit in CMD1A, but key questions must be answered before the potential of anti-apoptosis therapy is fully understood. We propose three sets of experiments to advance our understanding of anti- apoptosis approaches to therapy in neuromuscular diseases. For Specific Aim 1, we will use the Lama2-nu\\ mouse model to test known anti-apoptosis drugs, such as minocycline and caspase inhibitors, as potential pharmacological therapies for CMD1A. For Aim 2, we will combine different types of interventions, e.g. Bax inactivation and IGF-1 treatment, to examine mechanisms of pathogenesis and identify improved therapies. For Aim 3, we will determine if additional myopathies with respiratory muscle involvement, specifically those caused by loss of 8-or y-sarcoglycan, can be ameliorated by targeted alterations of Bcl-2 family members. Our goals are to extend our understanding of mechanisms of pathogenesis in muscle diseases and to lay the groundwork necessary for translation of anti-apoptosis therapies into clinical practice. Lay summary: Our work will evaluate a therapeutic strategy for specific neuromuscular diseases. These diseases are highly debilitating and currently have poor treatment options.


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 = $554,245 )
2010	2010	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	000	11	2/19/2010	NON-COMPETING CONTINUATION	$554,245
														Subtotal = $554,245

Issue Date FY: 2009 ( Subtotal = $549,087 )
2009	2009	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	001	10	3/31/2009	NON-COMPETING CONTINUATION	$52,745
2009	2009	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	002	10	4/8/2009	NON-COMPETING CONTINUATION	$21,639
2009	2009	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	000	10	2/20/2009	NON-COMPETING CONTINUATION	$474,703
														Subtotal = $549,087

Issue Date FY: 2008 ( Subtotal = $501,842 )
2008	2008	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	000	9	2/29/2008	NON-COMPETING CONTINUATION	$501,842
														Subtotal = $501,842

Issue Date FY: 2007 ( Subtotal = $497,166 )
2007	2007	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	000	8	3/1/2007	NON-COMPETING CONTINUATION	$497,166
														Subtotal = $497,166

Issue Date FY: 2006 ( Subtotal = $526,864 )
2006	2006	BOSTON BIOMEDICAL RESEARCH INSTITUTE	64 GROVE STREET	WATERTOWN	MA	02472	MIDDLESEX	USA	Lung Diseases Research	000	7	4/17/2006	COMPETING CONTINUATION	$526,864
														Subtotal = $526,864

Issue Date FY: 2004 ( Subtotal = $472,950 )
2004	2004	BOSTON BIOMEDICAL RESEARCH INSTITUTE							Lung Diseases Research	000	6	6/7/2004	NON-COMPETING CONTINUATION	$472,950
														Subtotal = $472,950

Issue Date FY: 2003 ( Subtotal = $472,950 )
2003	2003	BOSTON BIOMEDICAL RESEARCH INSTITUTE							Lung Diseases Research	000	5	6/25/2003	NON-COMPETING CONTINUATION	$472,950
														Subtotal = $472,950

Issue Date FY: 2002 ( Subtotal = $472,950 )
2002	2002	BOSTON BIOMEDICAL RESEARCH INSTITUTE							Lung Diseases Research	000	4	6/10/2002	NON-COMPETING CONTINUATION	$472,950
														Subtotal = $472,950

Issue Date FY: 2001 ( Subtotal = $381,950 )
2001	2001	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Lung Diseases Research	000	2	6/22/2001	NON-COMPETING CONTINUATION	$381,950
														Subtotal = $381,950

Issue Date FY: 2000 ( Subtotal = $377,650 )
2000	2000	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Lung Diseases Research	000	1	3/27/2000	NEW	$377,650
														Subtotal = $377,650

Grand Total All Awards = $4,807,654

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MOLECULAR PHYSIOLOGY OF RESPIRATORY MUSCLES

Award Number: R01HL064641

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2000

PERIOD OF PERFORMANCE END DATE: 02/28/2011

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