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Novel Notch regulation in KSHV reactivation

Award Number: R21AI150230
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Novel Notch regulation in KSHV reactivation - Project Description/Abstract Defining the molecular interactions between a virus and its host that regulate gene-specific transactivation has been essential to understanding DNA virus persistence and replication. The Kaposi’s sarcoma-associated Herpesivrus Rta protein is necessary and sufficient for the virus to emerge from latency and replicate (lytic reactivation). Rta interacts directly with the cellular protein called RBP-Jk, which is also required for lytic reacti- vation. RBP-Jk normally specifies the genes that will be activated by the cellular Notch signal transduction pathway by binding sequence specifically to DNA. In this fashion, RBP-Jk serves as a “landing pad” for the activated Notch receptor (Notch intracellular domain (NICD1)). KSHV Rta stimulates DNA binding of RBP-Jk during viral reactivation, a mechanism that is fundamentally different from the canonical mechanism established for other RBP-Jk-activating proteins, namely NICD1 and Epstein-Barr Virus (EBV) EBNA-2. Indeed, NICD1 is unable to stimulate complete viral reactivation, supporting a promoter-specific mechanism for controlling its activity in KSHV infected cells. Recent data suggest that DNA binding of RBP-Jk is regulated both positively and negatively in response to KSHV reactivation signals. Modulation of DNA binding of RBP-Jk is a novel level of regulation of the Notch pathway that has been underappreciated in the literature. The overall goal of this application is to define the basic molecular mechanisms that regulate RBP-Jk DNA binding in KSHV infected cells, and determine the transcriptional reprogramming that supports viral reactivation. Our studies will explain the fundamental regulation of productive and non-productive virus reactivation as determined by promoter- specific transactivation. We will therefore address these Specific Aims: Aim 1. Determine if novel host proteins stimulate Jk binding to viral promoters during KSHV reactivation. Aim 2. Determine how specific MBP/Jk/DNA complexes program Rta and Notch-dependent reactivation. A series of biochemical and molecular biological approaches are proposed. Protein-DNA interactions represent the basis for many of the experiments, and will be evaluated in response to overexpression or functional deletion of cellular proteins (termed ‘motif binding proteins’, or MBPs). Effects on viral reactivation will be quantitated using a novel, highly quantitative, KSHV reporter virus. A major part of the project involves using a novel version of Rta to detect and measure its direct targets by next generation sequencing. This proposal will shed light on how Notch target genes are specified for transactivation, and reveal new components of the Notch signal transduction pathway.


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: 2025 ( Subtotal = $0 )
2025	2021	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	1/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	5/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $196,250 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	7/2/2021	NON-COMPETING CONTINUATION	$196,250
														Subtotal = $196,250

Issue Date FY: 2020 ( Subtotal = $234,000 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	6/19/2020	NEW	$234,000
														Subtotal = $234,000

Grand Total All Awards = $430,250

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Novel Notch regulation in KSHV reactivation

Award Number: R21AI150230

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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