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Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome

Award Number: R01AI146380
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/07/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome - ABSTRACT DNA damage-mediated genome instability is a contributing factor in the causation of human diseases, including neurodegeneration, immunological disorders, and cancer. Understanding how cells prevent and manage DNA damage is highly significant. R loop, a transcription-linked 3 nucleic-acid structure consisting of a RNA:DNA hybrid and a displaced single-strand DNA (ssDNA), when decorated with histone H3S10p mark causes genomic instability upon its cleavage into DNA double strand breaks (DSBs). Currently, nothing is known about R loop dysfunction in the causation of human primary immunodeficiency disorders (PIDDs), aka, inborn errors of immunity. Using a PID disease model of human Wiskott-Aldrich syndrome (WAS), we recently discovered an essential nuclear role of WASp, the protein deficient in WAS, in limiting R loop-mediated DNA damage in CD4+ T helper 1 (Th1) lymphocytes. This discovery has opened up a new avenue of research into how WASp, a nucleocytoplasmic protein with dual-roles in F-actin polymerization and gene transcription, ensures R loop-linked genome stability. The current proposal seeks to define the nuclear signaling pathways and mechanisms involved in ensuring a healthy R loop balance, and therefore a stable genome, in human Th cells, and how their disruptions by WAS gene mutations is causally-linked to the development of immune deficiency and clinical phenotypes in WAS. Aim 1 focuses on defining chromatin-based mechanisms by which WASp influences the balance between beneficial (“good”) R loops and deleterious (“bad”) R loops, and their effects in the causation of WAS Th1 and WAS Th2 cellular phenotypes. Aim 2 will clarify the mechanism of the newly identified mRNA splicing defect in WAS Th cells as it relates to R loop formation and genome instability. Aim 3 will utilize primary T cells from multiple WAS patients of differing clinical severities to establish R loop load in the T cells as a “dynamic” disease biomarker, and to define the involvement of nuclear-F-actin effects of WASp in WAS phenotype development. In the long-term, the knowledge gained from these studies will foster the development of novel prognostics, diagnostics, and therapeutics for this PID and other R loop-mediated immunological disorders.


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 = $414,172 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	5	1/10/2024	NON-COMPETING CONTINUATION	$372,756
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	001	5	5/28/2024	NON-COMPETING CONTINUATION	$41,416
														Subtotal = $414,172

Issue Date FY: 2023 ( Subtotal = $424,706 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	000	4	1/13/2023	NON-COMPETING CONTINUATION	$424,706
														Subtotal = $424,706

Issue Date FY: 2022 ( Subtotal = $434,941 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	001	3	2/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$434,941
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Allergy and Infectious Diseases Research	003	3	6/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$7,160
2022	2021	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	002	2	6/10/2022	NON-COMPETING CONTINUATION	-$7,160
2022	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	2/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $434,941

Issue Date FY: 2021 ( Subtotal = $418,448 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	1/25/2021	NON-COMPETING CONTINUATION	$418,448
														Subtotal = $418,448

Issue Date FY: 2020 ( Subtotal = $424,875 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	2/7/2020	NEW	$424,875
														Subtotal = $424,875

Grand Total All Awards = $2,117,142

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Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome

Award Number: R01AI146380

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/07/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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