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Ca Signaling in Progression of Amyotrophic Lateral Sclerosis in Skeletal Muscle

Award Number: R01AR057404
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder involving degeneration of motor neurons and atrophy of skeletal muscle. Mutations in the superoxide dismutase (SOD1) gene are linked to most cases of inherited ALS, resulting in impaired metabolic function of the mitochondria. Currently, there is a lack of knowledge on how dysfunctional mitochondria and altered Ca signaling contribute to muscle degeneration during ALS progression. This new investigator initiated research project will test the hypothesis that "during the development of ALS, action potential activity at the neuromuscular junction (NMJ) will cause local Ca overload in mitochondria compromised by the presence of mutant SOD1. This overload will further disrupt mitochondria-sarcoplasmic reticulum (SR) coupling and lead to altered Ca and reactive oxygen species (ROS) signaling. The alteration in turn will increase local Ca, reinforcing the local deficit, thus constituting a primary event in the pathophysiology of ALS muscle". The central theme of our studies is to develop a comprehensive understanding of the cellular mechanism that contributes to the progressive decline in mitochondria-SR coupling leading to the compromised Ca homeostatic capacity of ALS muscle. We anticipate that information obtained from our research will apply to other neuromuscular diseases, such as aging, diabetes, Parkinson's disease and others, where altered Ca signaling and intracellular oxidative stress are linked to dysfunctional muscle contractility and altered motor neuron communication. In Aim 1, we propose to quantify the mitochondrial contribution to local control of SR Ca signaling, and use this quantification to evaluate how defective mitochondria-SR coupling contributes to progression of muscle wasting in ALS. By characterizing the changes in Ca signaling and mitochondrial function in skeletal muscle at different stages of ALS progression, our studies should provide a mechanistic understanding of how local control of SR Ca signaling is altered by mitochondria, how this process is altered in ALS muscle and what is the influence of axonal withdrawal in disrupting SR-mitochondria coupling leading to the progressive decline of muscle function in ALS. In Aim 2, we propose to use localized mitochondrial superoxide (O2-) FLASH signal as an index for mitochondrial metabolic function in ALS muscle, and to examine the effect of denervation on the interplay between mitochondria-SR in controlling intracellular Ca release and local O2- levels during the progression of muscle atrophy in ALS. These studies will reveal the role of localized coupling between Ca and O2- production in muscle physiology, and establish the cellular mechanism(s) that contribute to NMJ remodeling and the progressive development of muscle pathology in ALS.


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: 2017 ( Subtotal = $0 )
2017	2014	KANSAS CITY UNIVERSITY OF MEDICINE AND BIOSCIENCES	1750 INDEPENDENCE AVE	KANSAS CITY	MO	64106	JACKSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	12/9/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $5,133 )
2015	2014	KANSAS CITY UNIVERSITY OF MEDICINE AND BIOSCIENCES	1750 INDEPENDENCE AVENUE	KANSAS CITY	MO	64106	JACKSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	2/20/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$165,546
2015	2014	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/19/2015	NON-COMPETING CONTINUATION	-$160,413
														Subtotal = $5,133

Issue Date FY: 2014 ( Subtotal = $317,520 )
2014	2014	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/2/2014	NON-COMPETING CONTINUATION	$317,520
														Subtotal = $317,520

Issue Date FY: 2013 ( Subtotal = $307,800 )
2013	2013	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	2/22/2013	NON-COMPETING CONTINUATION	$291,600
2013	2013	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	7/14/2013	NON-COMPETING CONTINUATION	$16,200
														Subtotal = $307,800

Issue Date FY: 2012 ( Subtotal = $324,000 )
2012	2012	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/26/2012	NON-COMPETING CONTINUATION	$324,000
														Subtotal = $324,000

Issue Date FY: 2011 ( Subtotal = $321,192 )
2011	2011	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/8/2011	NON-COMPETING CONTINUATION	$20,074
2011	2011	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/11/2011	NON-COMPETING CONTINUATION	$301,118
														Subtotal = $321,192

Issue Date FY: 2010 ( Subtotal = $328,500 )
2010	2010	RUSH-PRESBYTERIAN-ST LUKE'S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/15/2010	NEW	$328,500
														Subtotal = $328,500

Grand Total All Awards = $1,604,145

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Ca Signaling in Progression of Amyotrophic Lateral Sclerosis in Skeletal Muscle

Award Number: R01AR057404

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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