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ATM and DNA Damage in the Nervous System

Award Number: R01NS037956
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract. Genome stability is critically important for human health. This is apparent from the myriad of inherited human syndromes characterized by defective DNA damage responses. The nervous system is particularly prone to the consequences of genome damage, which can lead to neurodegeneration or neurodevelopmental disorders. Defects in genome maintenance are also increasingly being linked to broader neurologic health issues, including age-related neurodegenerative events that mar cognitive ability and quality of life. Therefore, understanding the mechanistic connections between faulty DNA damage signaling and human disease is of fundamental biomedical importance. The neurodegenerative syndrome ataxia telangiectasia (A-T), which results from loss of function of the DNA damage-signaling serine/threonine kinase ATM (ataxia telangiectasia, mutated), exemplifies the importance of genome stability in the nervous system. However, despite intense interest in the molecular details of ATM function, its role in the nervous system remains elusive, as little is known about the genomic lesions or key substrates that activate ATM in an in vivo neural setting. We recently showed that ATM is critical for preventing the accumulation of Topoisomerase-1-DNA cleavage complexes (Top1cc) in the nervous system, which can lead to DNA strand breaks. This pathogenic Topoisomerase-1-DNA lesion directly impacts genome stability and may underpin disease etiology in A-T and other related neurodegenerative syndromes. Our studies have also revealed that elevation of DNA damage associated with ATM loss results in transcriptional disruption of essential cerebellar genes via the occurrence of pathogenic R-loops, a DNA/RNA intermediate that can form during transcription. These data have lead to our hypothesis that aberrant topoisomerase activity and causally related R-loops are etiologic genotoxins contributing to neurodegeneration in A-T and related disorders. Many genome stability factors (including ATM) that regulate topoisomerase function or restrain R-loop formation are linked to neurologic disease, suggesting a critical regulatory genome maintenance axis that prevents these potentially damaging lesions from causing neurodegeneration. During the prior grant cycle we developed multiple unique mouse models with which to interrogate ATM function, and to determine the pathogenic impact of specific genome lesions in the nervous system. These unique mouse models are central to the experiments proposed in this application. Amongst these is an inducible Topoisomerase-1 mutation that promotes formation of Top1cc in the nervous system, which synergizes strongly with ATM loss to cause cerebellar dysfunction and ataxia. This proposal will provide substantial new information to enhance our understanding of the central mechanisms that maintain the neural genome. Moreover, data from this work will provide important groundwork for the eventual development of therapeutic approaches to treat neurological disease resulting from genome instability.


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: 2023 ( Subtotal = -$109,374 )
2023	2017	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	10/1/2022	NON-COMPETING CONTINUATION	-$109,374
														Subtotal = -$109,374

Issue Date FY: 2022 ( Subtotal = $392,656 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	1/6/2022	NON-COMPETING CONTINUATION	$353,390
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	23	4/15/2022	NON-COMPETING CONTINUATION	$39,266
														Subtotal = $392,656

Issue Date FY: 2021 ( Subtotal = $392,656 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	3/4/2021	NON-COMPETING CONTINUATION	$392,656
														Subtotal = $392,656

Issue Date FY: 2020 ( Subtotal = $392,656 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	3/12/2020	NON-COMPETING CONTINUATION	$392,656
														Subtotal = $392,656

Issue Date FY: 2019 ( Subtotal = $392,656 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	1/18/2019	NON-COMPETING CONTINUATION	$392,656
														Subtotal = $392,656

Issue Date FY: 2018 ( Subtotal = $392,656 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	1/26/2018	COMPETING CONTINUATION	$392,656
2018	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	6/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,656

Issue Date FY: 2017 ( Subtotal = $421,095 )
2017	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	1/27/2017	NON-COMPETING CONTINUATION	$344,531
2017	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	18	6/6/2017	NON-COMPETING CONTINUATION	$38,282
2017	2016	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	1/30/2017	EXTENSION WITH OR WITHOUT FUNDS	$38,282
														Subtotal = $421,095

Issue Date FY: 2016 ( Subtotal = $344,531 )
2016	2016	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	1/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$344,531
														Subtotal = $344,531

Issue Date FY: 2015 ( Subtotal = $382,813 )
2015	2015	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	1/15/2015	NON-COMPETING CONTINUATION	$382,813
														Subtotal = $382,813

Issue Date FY: 2014 ( Subtotal = $378,985 )
2014	2014	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	3/10/2014	NON-COMPETING CONTINUATION	$34,454
2014	2014	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	1/7/2014	NON-COMPETING CONTINUATION	$344,531
														Subtotal = $378,985

Issue Date FY: 2013 ( Subtotal = $382,813 )
2013	2013	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	1/31/2013	COMPETING CONTINUATION	$382,813
2013	2011	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	1/22/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $382,813

Issue Date FY: 2011 ( Subtotal = $375,156 )
2011	2011	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/14/2011	NON-COMPETING CONTINUATION	$375,156
														Subtotal = $375,156

Issue Date FY: 2010 ( Subtotal = $374,023 )
2010	2010	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	9/1/2010	NON-COMPETING CONTINUATION	$10,197
2010	2010	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	8/3/2010	NON-COMPETING CONTINUATION	$363,826
														Subtotal = $374,023

Issue Date FY: 2009 ( Subtotal = $367,500 )
2009	2009	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	6/19/2009	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2008 ( Subtotal = $367,501 )
2008	2008	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/21/2008	COMPETING CONTINUATION	$367,501
														Subtotal = $367,501

Issue Date FY: 2006 ( Subtotal = $347,879 )
2006	2006	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/15/2006	NON-COMPETING CONTINUATION	$347,879
														Subtotal = $347,879

Issue Date FY: 2005 ( Subtotal = $356,250 )
2005	2005	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	8/22/2005	NON-COMPETING CONTINUATION	$356,250
														Subtotal = $356,250

Issue Date FY: 2004 ( Subtotal = $356,250 )
2004	2004	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/19/2004	NON-COMPETING CONTINUATION	$356,250
														Subtotal = $356,250

Issue Date FY: 2003 ( Subtotal = $356,250 )
2003	2003	ST JUDE CHILDREN'S RESEARCH HOSPITAL	POST OFFICE BOX 318	MEMPHIS	TN	38101	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/15/2003	NON-COMPETING CONTINUATION	$356,250
														Subtotal = $356,250

Issue Date FY: 2002 ( Subtotal = $356,250 )
2002	2002	ST JUDE CHILDREN'S RESEARCH HOSPITAL	POST OFFICE BOX 318	MEMPHIS	TN	38101	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/27/2002	COMPETING CONTINUATION	$356,250
														Subtotal = $356,250

Issue Date FY: 2001 ( Subtotal = $216,478 )
2001	2001	ST JUDE CHILDREN'S RESEARCH HOSPITAL	POST OFFICE BOX 318	MEMPHIS	TN	38101	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/23/2001	NON-COMPETING CONTINUATION	$216,478
														Subtotal = $216,478

Issue Date FY: 2000 ( Subtotal = $210,176 ) (Continued on the next page)
Grand Total All Awards = $7,850,021

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ATM and DNA Damage in the Nervous System

Award Number: R01NS037956

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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