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Understanding How the Ubiquitin Ligase CBL Regulates Innate Immune Responses

Award Number: R01AI144149
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: 09/19/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Understanding How the Ubiquitin Ligase CBL Regulates Innate Immune Responses - PROJECT SUMMAY/ABSTRACT This is an application for an NIH R01 Research Project Grant. Our long-term goal is to determine how Mycobacterium tuberculosis (Mtb) disrupts the host immune response to establish infection in humans, and to use this information to develop better vaccines and therapies for tuberculosis (TB). In our prior work, we used proteomics to systematically define the interactions between secreted Mtb proteins and human proteins, and discovered a network of several hundred highly-specific interactions that potentially play important roles in Mtb pathogenesis and host defense. We began an initial genetic analysis of the interaction network, and discovered both a novel virulence factor LpqN, as well as its probable host target, the ubiquitin ligase CBL. The specific goal of this application is to study the mechanisms by which CBL regulates innate immune signaling in macrophages and in mice. In Aim 1 we will use biochemical analyses to test the hypothesis that CBL ubiquitylates IRF3 and/or IRF7, targeting them for degradation and thus suppressing antiviral responses. If this hypothesis is incorrect we will take more global approaches to identifying CBL substrates. In Aim 2 we will determine the mechanism by which the virulence factor LpqN disrupts CBL function to promote Mtb growth. In Aim 3 we will explore the function of a novel phosphorylation event we have identified on serine 450 of CBL. These findings will pave the way for future studies that will seek to uncover the molecular mechanisms by which these host factors contribute to immunity and may suggest ways that the factors can be manipulated for therapeutic benefit.


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	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	5	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $467,974 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	5	8/1/2023	NON-COMPETING CONTINUATION	$467,974
														Subtotal = $467,974

Issue Date FY: 2022 ( Subtotal = $493,094 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	4	8/9/2022	NON-COMPETING CONTINUATION	$493,094
														Subtotal = $493,094

Issue Date FY: 2021 ( Subtotal = $496,104 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	3	8/12/2021	NON-COMPETING CONTINUATION	$496,104
														Subtotal = $496,104

Issue Date FY: 2020 ( Subtotal = $477,394 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	2	8/11/2020	NON-COMPETING CONTINUATION	$477,394
														Subtotal = $477,394

Issue Date FY: 2019 ( Subtotal = $457,376 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	1	9/19/2019	NEW	$457,376
														Subtotal = $457,376

Grand Total All Awards = $2,391,942

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Understanding How the Ubiquitin Ligase CBL Regulates Innate Immune Responses

Award Number: R01AI144149

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: 09/19/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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