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Determining the role of lipooligosaccharide on the Opa structural ensemble and the formation of an Opa-CEACAM complex

Award Number: F32GM136076
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Determining the role of lipooligosaccharide on the Opa structural ensemble and the formation of an Opa-CEACAM complex - Project Summary Neisseria gonorrhoeae (Gc) and Neisseria meninigitidis (Nm) are pathogenic bacteria causing the sexually transmitted infection gonorrhea and meningococcal meningitis respectively. Gc is a seriously world-wide health concern, especially considering the rise of antibiotic resistance in Gc strains. Nm is a less severe threat, however development of vaccines and antibiotics to prevent and treat Nm infection is still needed. Understanding Neisseria infection and pathogen-host interactions at the basic molecular level becomes crucial for these essential tasks. Opacity-associated (Opa) proteins in Neisseria are known to trigger engulfment of the bacteria into human cells via their interaction with members of the carcinoembryonic antigen-related cellular adhesion molecule (CEACAM or CCM) family. The structure of Opa has been characterized by our lab, but attempts to characterize the Opa-CCM molecular complex have conflicted with the established knowledge of the field. There is evidence that lipooligosaccharide (LOS), a dominant component of the neisserial outer membrane, can bind Opa proteins on adjacent bacteria, and that changes in LOS structure can affect bacterial opacity, Opa expression, Opa-CCM interactions, and Neisseria survival. For these reasons, I hypothesize that lipooligosaccharide is an important factor in Neisseria for maintenance of Opa loop structure, for facilitating Opa-CCM complex formation and for triggering engulfment of Neisseria via Opa-CCM interaction, and may be an essential molecular piece we have been missing in our previous experimental characterization. I propose to build upon the lab’s expertise with Opa and CCM proteins to (i) determine the role of LOS on the Opa protein and the structural assembly of Opa’s characteristic dynamic and hypervariable loops (Aim 1) and (ii) to assess the effect of LOS on the affinity of the Opa-CCM complex formation and its ability to trigger engulfment in human cells in a CCM-dependent manner. I will take a biophysical approach to Aim 1, utilizing spectroscopic techniques to characterize any change in Opa’s conformational heterogeneity or secondary structure in the presence of LOS, which will be a large part of my training. In a world-class environment, I will be trained in electron paramagnetic resonance (EPR) spectroscopic techniques, circular dichroism and nuclear magnetic resonance (NMR) spectroscopy. In Aim 2, I will combine biochemical and cell-based approaches to characterize the effect of LOS on Opa-CCM protein complex formation and cellular uptake. This experimental approach will supplement my biophysical training and help me become a well-rounded scientist who can tackle complex biological questions with an arsenal of techniques. By describing the molecular basis for Opa-CCM interaction, we will provide a more solid foundation for the development of novel vaccines and antibiotics to the broader community studying Neisseria infection.


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: 2024 ( Subtotal = -$2,246 )
2024	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	3	12/28/2023	NON-COMPETING CONTINUATION	-$2,246
														Subtotal = -$2,246

Issue Date FY: 2022 ( Subtotal = $70,360 )
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	3	1/21/2022	NON-COMPETING CONTINUATION	$69,120
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	3	6/6/2022	NON-COMPETING CONTINUATION	$1,240
														Subtotal = $70,360

Issue Date FY: 2021 ( Subtotal = $66,948 )
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	2	1/25/2021	NON-COMPETING CONTINUATION	$65,868
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	2	2/9/2021	NON-COMPETING CONTINUATION	$1,080
														Subtotal = $66,948

Issue Date FY: 2020 ( Subtotal = $65,484 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	1	2/17/2020	NEW	$3,700
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	002	1	2/17/2020	NEW	$0
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	1	12/19/2019	NEW	$61,784
														Subtotal = $65,484

Grand Total All Awards = $200,546

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Determining the role of lipooligosaccharide on the Opa structural ensemble and the formation of an Opa-CEACAM complex

Award Number: F32GM136076

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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