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The functions of the zinc finger protein ZPR1 in R-loop metabolism and neurodegeneration.

Award Number: R01NS115834
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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PROJECT SUMMARY The goal of this study is to examine the functions of the zinc finger protein ZPR1 in R-loops metabolism and neurodegeneration. R-loops are formed during transcription and consist of RNA-DNA hybridized strands and a complementary DNA strand. R-loop accumulation results in DNA damage leading to neurodegeneration associated with genetic neurodegenerative diseases, including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). ZPR1 is evolutionary conserved in eukaryotes and is essential for cell viability. However, very little is known about the ZPR1 biological functions that may contribute to cell viability and human disease etiology. ZPR1 interacts directly with translation elongation factor 1A (EF1A), RNA Polymerase II and Senataxin (SETX), which are also conserved in eukaryotes. SETX is an RNA-DNA helicase required for resolution of R- loops. Mutations in SETX are associated with a group of untreatable neurodegenerative disorders, including ataxia oculomotor apraxia type 2, autosomal dominant SMA and ALS4, characterized by defects in R-loop metabolism. The molecular mechanisms of R-loop resolution are largely unknown. Our preliminary data show that ZPR1 deficiency causes R-loop accumulation and neurodegeneration. ZPR1 overexpression reduces R- loops and rescues DNA damage in neurons and patient cells, and prevents neurodegeneration in SMA mice. ZPR1 binds to RNA-DNA hybrids and associates with R-loops in vivo. ZPR1 interacts with SETX and ZPR1 is required for the formation of SETX complexes with R-loops suggesting that ZPR1 may help recruit SETX to R- loops. We have created novel Zpr1 mutant mice, with double and quadruple point mutations in the Zpr1 locus to selectively disrupt ZPR1-EF1A complexes. ZPR1 mutant mice show accumulation of R-loops and develop neurodegenerative disease-like phenotypes similar to reported for patients with SETX mutations. Together, these findings raise a hypothesis that ZPR1 complexes with EF1A and SETX may play distinct and critical roles in R-loop resolution and provide a foundation for investigating the function of ZPR1-EF1A and ZPR1-SETX complexes in R-loop metabolism. The specific aims are to examine: (Aim 1) the molecular basis of ZPR1- dependent accumulation of co-transcriptional R-loops and neurodegeneration using Zpr1 conditional mice; (Aim 2) the function of ZPR1-EF1A complexes in R-loop resolution using novel mouse models to disrupt ZPR1-EF1A complexes in vivo in motor neurons that we have generated, and the mechanism of GTP/GDP-dependent resolution of RNA and DNA strands by ZPR1-EF1A complexes; (Aim 3) the function of ZPR1-SETX complexes in R-loop metabolism, genome integrity and ALS4 pathogenesis. ZPR1-SETX complexes are disrupted in ALS4 patients with SETX mutation. The effect of disruption of ZPR1-SETX complexes on R-loop metabolism, DNA replication fork and genome integrity using cell-based models, including patient cells. This study will provide comprehensive insight into the molecular basis of pathogenesis caused by defects in R-loop metabolism that would be a breakthrough towards developing targeted therapeutic strategies for a group of incurable 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: 2024 ( Subtotal = $0 )
2024	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	10/30/2023	NON-COMPETING CONTINUATION	-$1
2024	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	4	10/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$780,631
2024	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	4	7/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	2	10/30/2023	SUPPLEMENT FOR EXPANSION	-$251,195
2024	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	10/30/2023	NON-COMPETING CONTINUATION	-$424,271
2024	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	10/30/2023	NEW	-$88,647
2024	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	10/30/2023	SUPPLEMENT FOR EXPANSION	-$16,516
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $421,374 )
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	7/17/2023	NON-COMPETING CONTINUATION	-$418,608
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/9/2023	NON-COMPETING CONTINUATION	$376,749
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/1/2023	NON-COMPETING CONTINUATION	$41,860
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	7/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$421,373
														Subtotal = $421,374

Issue Date FY: 2022 ( Subtotal = $675,466 )
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/7/2022	NON-COMPETING CONTINUATION	$381,846
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/28/2022	NON-COMPETING CONTINUATION	$42,425
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	6/29/2022	SUPPLEMENT FOR EXPANSION	$251,195
														Subtotal = $675,466

Issue Date FY: 2021 ( Subtotal = $527,702 )
2021	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	7/14/2021	SUPPLEMENT FOR EXPANSION	$82,877
2021	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/29/2021	NEW	$0
2021	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/31/2020	NEW	$444,825
														Subtotal = $527,702

Grand Total All Awards = $1,624,542

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The functions of the zinc finger protein ZPR1 in R-loop metabolism and neurodegeneration.

Award Number: R01NS115834

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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