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The function of chemotactic signal transduction during colonization and disease

Award Number: R01AI116946
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: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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The function of chemotactic signal transduction during colonization and disease - Our proposed research focuses on defining the mechanism of action of the TlpC chemoreceptor in modulating colonization and pathogenesis of the ulcer-causing bacterium Helicobacter pylori. TlpC plays important and exciting roles in H. pylori pathogenesis, sensing host lactate and allowing H. pylori to use it to resist a previ- ously-unappreciated innate immune challenge, complement. The central tenet that guides this work is that un- derstanding chemotaxis signals will lend new insight into the nature of host-pathogen interactions. A gap re- mains, however in our understanding of how H. pylori uses lactate to promote complement resistance, how TlpC integrates lactate and other ligand sensing, and how and where TlpC-mediated sensing promotes in vivo growth. Continued existence of this gap prevents us from gaining a full understanding of H. pylori’s pathogenic mechanisms and, in the long term, creating new drugs to thwart these processes. Millions of people worldwide and in the U.S. are infected by H. pylori and suffer from its associated diseases—ulcers and gastric cancer. Gastric cancer is the fourth highest cause of cancer deaths worldwide. H. pylori is here to stay based on recent studies that show H. pylori incidence has stabilized in the developed world. Furthermore, current therapies to cure H. pylori infection fail with unacceptable frequency, e.g., recent estimates in the United States have found that 20-25% of infected individuals are not cured by the current therapeutic regime. New drug targets are des- perately needed. The specific objective of this application is to dissect TlpC signal transduction and the role of it and its sensed compounds in gastric colonization and disease. Our central hypothesis is that the TlpC- sensed compounds play fundamental roles in H. pylori colonization, and are sensed cooperatively using both subdomains of TlpC’s dCACHE ligand binding domain structure. Our hypothesis has been formulated from preliminary data using crystallization of TlpC, analyzing H. pylori ’s response to lactate and host complement, and determining the role of chemotaxis and TlpC in vivo. Our approach has three Aims, which combine H. py- lori molecular biology, mouse models, and high resolution protein crystallography. In Aim 1, we dissect the role of lactate in H. pylori colonization including how it promotes growth and complement resistance. In Aim 2, we determine how H. pylori TlpC integrates information from multiple ligands into a chemotaxis response. In Aim 3, we define how chemotaxis underlies in vivo population control. The proposed research is innovative in that it will create new knowledge about the functions of chemotaxis during bacterial pathogenesis, the role of comple- ment in the stomach, and high resolution information about how dCACHE ligand binding domains bind ligands. The proposed research is significant because both in our understanding of H. pylori pathogenesis but also for advancing our understanding of dCACHE ligand binding domains, the most common bacterial sensing module. The long-term outcomes generated by this research are likely to provide insights that will enable creation of new drugs against H. pylori-related disease.


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 = $460,167 )
2025	2025	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	003	10	8/21/2025	SUPPLEMENT FOR EXPANSION	$14,320
2025	2025	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	002	10	8/19/2025	NON-COMPETING CONTINUATION	$445,847
2025	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	9	4/21/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	001	9	7/9/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $460,167

Issue Date FY: 2024 ( Subtotal = $608,856 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	001	9	7/29/2024	NON-COMPETING CONTINUATION	$445,847
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	002	9	8/14/2024	SUPPLEMENT FOR EXPANSION	$88,834
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	8	11/20/2023	SUPPLEMENT FOR EXPANSION	$74,175
														Subtotal = $608,856

Issue Date FY: 2023 ( Subtotal = $430,025 )
2023	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	8	8/15/2023	NON-COMPETING CONTINUATION	$430,025
														Subtotal = $430,025

Issue Date FY: 2022 ( Subtotal = $427,683 )
2022	2022	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	002	7	8/18/2022	NON-COMPETING CONTINUATION	$427,683
2022	2021	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	001	6	6/9/2022	COMPETING CONTINUATION	$16,471
2022	2020	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	5	6/9/2022	NON-COMPETING CONTINUATION	-$16,471
														Subtotal = $427,683

Issue Date FY: 2021 ( Subtotal = $439,479 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	001	6	9/17/2021	COMPETING CONTINUATION	$439,479
2021	2020	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	5	9/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $439,479

Issue Date FY: 2020 ( Subtotal = $516,946 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	5	12/5/2019	NON-COMPETING CONTINUATION	$516,946
														Subtotal = $516,946

Issue Date FY: 2019 ( Subtotal = $615,779 )
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	4	11/26/2018	NON-COMPETING CONTINUATION	$536,058
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	002	4	6/27/2019	SUPPLEMENT FOR EXPANSION	$36,078
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	001	4	6/12/2019	SUPPLEMENT FOR EXPANSION	$43,643
														Subtotal = $615,779

Issue Date FY: 2018 ( Subtotal = $538,358 )
2018	2018	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	3	11/22/2017	NON-COMPETING CONTINUATION	$538,358
														Subtotal = $538,358

Issue Date FY: 2017 ( Subtotal = $534,498 )
2017	2017	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	2	11/23/2016	NON-COMPETING CONTINUATION	$534,498
														Subtotal = $534,498

Issue Date FY: 2016 ( Subtotal = $576,957 )
2016	2016	UNIVERSITY OF CALIFORNIA-SANTA CRUZ	1156 HIGH STREET	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	1	11/18/2015	NEW	$576,957
														Subtotal = $576,957

Grand Total All Awards = $5,148,748

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The function of chemotactic signal transduction during colonization and disease

Award Number: R01AI116946

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: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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