Thursday, November 21, 2024 11/21/2024

Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery

Award Number: R35GM131829
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Bacterial pathogens membrane proteins are important, and sometimes critical, to pathogenesis and, thus, human health. Despite the importance of these proteins in regulating host interactions, they are less understood than channels, transporters and GPCRs. The study of these proteins can, therefore, provide new knowledge about membrane protein structure, function, and dynamics, as well as have impact on combatting bacterial infections. These studies are particularly important because bacterial membrane proteins are frequent targets of antibiotics for which resistance is a growing threat. This MIRA application outlines our recent endeavors in understanding two bacterial membrane proteins: Opa and LspA, each of which is independently important for bacterial proliferation in humans. The overall goal of this proposal is to determine how these proteins look (beyond static structure), how they work, and how we can use this structure/function knowledge to advance our understanding of bacterial pathogenesis and human health. The outer membrane Opa proteins from Neisseria gonorrhoeae and N. meningitidis bind various host receptors and induce bacterial engulfment into human host cells. We have previously determined the monomeric structure of Opa60 and established that Opa-reconstituted liposomes engage in receptor-mediated phagocytosis. Future directions focus on a multidisciplinary approach to understanding the oligomeric structure of Opa60 and the Opa60-receptor complex. In another avenue of research, we focus on LspA, a membrane-embedded signal peptidase that processes essential lipoproteins in nearly all bacteria. Despite the relevance of LspA as a target for antibiotics, inhibitors of LspA are currently unavailable in the clinic. Interactions between LspA and its substrate differ among bacterial species, and we aim to investigate the structure and conformational changes of LspA with substrate and investigate the molecular determinants for substrate selectivity. Finally, this proposal outlines an emerging project that investigates bacterial membrane protein – lipid interactions. Bacterial inner membrane lipid composition varies significantly between bacterial species and the hypothesis that membrane proteins evolve and adapt to these lipid composition is tested.Results of the proposed aims will provide the molecular determinants of (i) neisserial Opa – Opa and Opa – host receptor interactions, (ii) substrate binding and recognition of LspA and (iii) membrane protein – lipid interactions. This knowledge will enhance our understanding of host-pathogen interactions and aid in combatting infections associated with bacterial pathogens.


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	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	6	11/4/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $435,032 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	6	5/29/2024	COMPETING CONTINUATION	$435,032
														Subtotal = $435,032

Issue Date FY: 2023 ( Subtotal = $381,538 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	5	5/9/2023	NON-COMPETING CONTINUATION	$381,538
														Subtotal = $381,538

Issue Date FY: 2022 ( Subtotal = $381,538 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	4	6/6/2022	NON-COMPETING CONTINUATION	$381,538
														Subtotal = $381,538

Issue Date FY: 2021 ( Subtotal = $381,538 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	3	4/29/2021	NON-COMPETING CONTINUATION	$381,538
														Subtotal = $381,538

Issue Date FY: 2020 ( Subtotal = $381,538 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	2	5/25/2020	NON-COMPETING CONTINUATION	$381,538
														Subtotal = $381,538

Issue Date FY: 2019 ( Subtotal = $328,540 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	1	4/24/2019	NEW	$328,540
														Subtotal = $328,540

Grand Total All Awards = $2,289,724

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Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery

Award Number: R35GM131829

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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