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Structural-functional studies of gingipain biogenesis and localization

Award Number: R01DE036286
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Structural-functional studies of gingipain biogenesis and localization - PROJECT SUMMARY There is an urgent need to explore new therapeutic approaches in the management of periodontitis, a prevalent and chronic disease that currently lacks effective treatment. Further, a growing number of studies have linked periodontitis to systemic diseases such as atherosclerosis or rheumatoid arthritis, as well as some cancers, diabetes, and Alzheimer’s disease. Porphyromonas gingivalis, a black-pigmented, Gram-negative anaerobe, is a keystone pathogen in microbial-induced periodontal disease. A comprehensive mechanistic understanding of some of its virulence factors is essential as the first step for therapeutic development. The bacterium uses a Type IV Secretion System to secrete an array of virulence factors, including gingipains [cysteine proteases – Arg-specific RgpA and RgpB, and Lys-specific Kgp], which are essential for its pathogenicity. There is still a significant gap in our understanding of the mechanism of post- translational proteolytic processing of progingipains and membrane surface assembly of non- covalent complexes composed of a catalytic domain and hemagglutinin (HA) domains. In addition, the role of HA domains in P. gingivalis pathogenesis is unclear. Our objective is to expand the understanding of the gingipains' hemagglutinating/adhesive properties and the formation of their surface complexes. The specific aims of the current application are designed for a comprehensive assessment of the gingipain structure-function properties, including its biogenesis and specific localization. Experiments are outlined to determine the post-translational sequential processing steps leading to the formation of gingipain complexes on the bacterial surface. We will conduct a comparative analysis of proteolytic activity, independent biological functions of single-chain pro gingipains, and assembly of native non-covalent complexes of the catalytic domain with HA domains. We will determine the structure of non-covalent gingipain surface complexes. Finally, we will dissect the functional roles of distinct hemagglutinin/adhesin domains in P. gingivalis adhesion and pathogenicity. A conceptual innovation is characterizing the structures of full-length gingipains and native RgpA-Kgp membrane complexes. This will shed new light on the cooperative mechanism of proteolytic cleavage and adhesion/hemagglutination activity exerted by gingipains. Given their specific bacterial surface localization, we posit that only simultaneous inhibition of both properties will lead to the development of effective drugs against periodontitis and P. gingivalis-driven systemic diseases.


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: 2026 ( Subtotal = $631,170 )
2026	2026	LOMA LINDA UNIVERSITY	11145 ANDERSON ST STE 203	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Oral Diseases and Disorders Research	000	1	7/21/2026	NEW	$631,170
														Subtotal = $631,170

Grand Total All Awards = $631,170

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Structural-functional studies of gingipain biogenesis and localization

Award Number: R01DE036286

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/21/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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