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Regulation of TLR trafficking for proper self versus non-self discrimination

Award Number: R01AI072429
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: 02/01/2008
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Regulation of TLR trafficking for proper self versus non-self discrimination - PROJECT SUMMARY Inappropriate recognition of self nucleic acids (NA) by members of the Toll-like receptor (TLR) family can result in autoimmune diseases such as lupus and psoriasis. TLR7 (and TLR8 in humans) and TLR9 can be activated by self RNA and DNA, respectively, so defining the mechanisms that limit responses by these TLRs is highly relevant to human health and disease. There is also accumulating evidence that the mechanisms controlling TLR7 and TLR9 responses are distinct, but our understanding of the molecular bases for these differences and their relevance for disease remain poor. This application is a renewal of the grant that has funded our research studying the regulation of NA-sensing TLRs for 15 years. Our prior work helped to establish the paradigm that multiple mechanisms operate to restrict the function of NA-sensing TLRs to endosomes, which limits recognition of self NAs released from dead cells into the extracellular space. In the last funding period, we made a major breakthrough that revealed a new mechanism mediated by the TLR chaperone Unc93b1 that limits TLR7 responses to self RNA, and we showed that disruption of this mechanism results in TLR7-dependent autoimmunity in mice. Intriguingly, this mechanism controls TLR7 but not TLR9. Our prior discoveries raise many key questions that we aim to tackle in this renewal application. We do not yet understand the molecular steps controlling the new mechanism of TLR7 regulation we discovered. Moreover, we recently identified autoimmune patients with in-born coding variants in Unc93b1, but we do not know if/how these variants cause disease. In this proposal we will also expand our studies of NA-sensing TLR regulation beyond Unc93b1 based on recently completed genome-wide CRISPR screens for genes that limit TLR7 and TLR9 responses. Both screens identified genes and pathways involved in core cell biological processes, including endosome and lysosome regulation, underscoring the paradigm that the cell biology of NA-sensing TLRs is critical to their regulation. However, the hits from the TLR7 and TLR9 screens are almost completely non-overlapping, providing exciting mechanistic insights into how these receptors are distinctly regulated. Based on these results, we propose 3 Specific Aims. Aim 1 will define the key steps by which Unc93b1 limits TLR7/8 responses and will test whether the human coding variants we have identified disrupt these steps. Aim 2 will characterize results from a genome-wide CRISPR screen that identified the cellular machinery and pathways limiting TLR7 responses to self RNA. Aim 3 will focus on TLR9 and begin to define the mechanisms that limit TLR9 responses to self DNA. The overall impact of this application comes from the central role that NA-sensing TLRs play in autoimmunity and from the benefit gained by defining the mechanisms that limit responses to self NA. Our central premise is that defining the mechanisms that regulate TLR7 and TLR9 will uncover their distinct roles in autoimmune diseases and enable more effective therapies.


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 = $524,936 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	17	12/18/2024	NON-COMPETING CONTINUATION	$524,936
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	002	16	1/20/2025	COMPETING CONTINUATION	$0
2025	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	15	1/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $524,936

Issue Date FY: 2024 ( Subtotal = $541,171 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	16	9/4/2024	COMPETING CONTINUATION	$54,119
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	16	2/14/2024	COMPETING CONTINUATION	$487,052
														Subtotal = $541,171

Issue Date FY: 2022 ( Subtotal = $441,142 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	15	8/4/2022	NON-COMPETING CONTINUATION	$441,142
														Subtotal = $441,142

Issue Date FY: 2021 ( Subtotal = $445,067 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	14	7/30/2021	NON-COMPETING CONTINUATION	$445,067
														Subtotal = $445,067

Issue Date FY: 2020 ( Subtotal = $448,992 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	13	8/14/2020	NON-COMPETING CONTINUATION	$448,992
														Subtotal = $448,992

Issue Date FY: 2019 ( Subtotal = $460,767 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	12	8/1/2019	NON-COMPETING CONTINUATION	$460,767
														Subtotal = $460,767

Issue Date FY: 2018 ( Subtotal = $469,426 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	11	9/21/2018	COMPETING CONTINUATION	$469,427
2018	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	10	6/19/2018	NON-COMPETING CONTINUATION	-$1
														Subtotal = $469,426

Issue Date FY: 2017 ( Subtotal = $392,500 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	10	1/12/2017	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2016 ( Subtotal = $392,500 )
2016	2016	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	9	1/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$392,500
														Subtotal = $392,500

Issue Date FY: 2015 ( Subtotal = $391,979 )
2015	2015	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	8	1/1/2015	NON-COMPETING CONTINUATION	$391,979
														Subtotal = $391,979

Issue Date FY: 2014 ( Subtotal = $391,250 )
2014	2014	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	7	1/8/2014	NON-COMPETING CONTINUATION	$352,125
2014	2014	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	7	6/9/2014	NON-COMPETING CONTINUATION	$39,125
														Subtotal = $391,250

Issue Date FY: 2013 ( Subtotal = $366,796 )
2013	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	6	6/11/2013	COMPETING CONTINUATION	$15,609
2013	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	6	1/11/2013	COMPETING CONTINUATION	$351,187
														Subtotal = $366,796

Issue Date FY: 2012 ( Subtotal = $323,795 )
2012	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	5	2/2/2012	NON-COMPETING CONTINUATION	$323,795
														Subtotal = $323,795

Issue Date FY: 2011 ( Subtotal = $325,133 )
2011	2011	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	4	1/7/2011	NON-COMPETING CONTINUATION	$295,574
2011	2011	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	4	6/3/2011	NON-COMPETING CONTINUATION	$29,559
														Subtotal = $325,133

Issue Date FY: 2010 ( Subtotal = $329,644 )
2010	2010	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	3	1/21/2010	NON-COMPETING CONTINUATION	$329,644
														Subtotal = $329,644

Issue Date FY: 2009 ( Subtotal = $432,566 )
2009	2009	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	2	6/2/2009	NON-COMPETING CONTINUATION	$33,367
2009	2009	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	2	1/6/2009	NON-COMPETING CONTINUATION	$300,309
2009	2009	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Trans-NIH Recovery Act Research Support	002	2	7/17/2009	SUPPLEMENT FOR EXPANSION	$98,890
														Subtotal = $432,566

Issue Date FY: 2008 ( Subtotal = $334,097 )
2008	2008	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	1	1/29/2008	NEW	$334,097
														Subtotal = $334,097

Grand Total All Awards = $7,011,761

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Regulation of TLR trafficking for proper self versus non-self discrimination

Award Number: R01AI072429

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: 02/01/2008

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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