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Canonical and non-canonical roles of the alternative pathway of complement in intestinal host defense

Award Number: DP2AI201039
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Canonical and non-canonical roles of the alternative pathway of complement in intestinal host defense - PROJECT SUMMARY The complement system is an evolutionarily conserved family of proteins that rapidly responds to infections and decreases pathogen burden. Genetic complement deficiencies are associated with recurrent bacterial infections. However, dysregulated activation of the complement system is associated with autoimmune disease as well as exuberant immune responses at mucosal surfaces, such as inflammatory bowel disease. A major hurdle in harnessing the complement system at mucosal surfaces is that key complement proteins involved in its activation are not only liver-derived and operative in the circulation, but are also produced locally within tissues. We and others have demonstrated the activity of complement components such as C3 and Factor B (CFB) at mucosal sites such as the gut, lungs, genitourinary tract and skin, which are exposed to various innocuous and at times deleterious antigens. Yet, a comprehensive understanding of cell type-specific sourcing of complement proteins, and their activation and regulation at mucosal sites, especially the gut, remains unknown. A major hurdle for investigating the tissue-specific roles of complement has been the limited availability of models and assays. I have developed key transgenic models and functional assays to separate the roles of circulating versus gut- derived complement proteins, which will help us delineate the role of complement in intestinal immunity. This proposal for the NIAID New Innovator Award is based in an overarching theme that at mucosal sites such as the gut, the high likelihood of external threats requires local rather than systemic complement activation and regulation to orchestrate homeostasis. To critically investigate this theme, I will pursue proteins from the alternative pathway of complement activation such as CFB, which is one of the most ancient complement proteins in evolution. I have identified that CFB has novel, non-canonical roles in the gut, which extends beyond its canonical roles of activating the complement cascade. I will dissect these non-canonical roles in intestinal epithelial cell maintenance using both in vivo and in vitro approaches, to determine the cell type-specific sourcing of complement at the intestinal barrier under homeostasis and under stress. I will also investigate how mucosal complement activity can be regulated to prevent tissue damage using novel therapeutic compounds. The proposed work is important because a deep understanding of how the early host immune response modulates tissue damage is essential for designing and implementing therapies to ameliorate mucosal inflammation. My studies seek to leverage the existing biology underlying local complement activation, which is critical for mounting an effective immune response, along with its novel non-canonical roles. These studies have the potential to identify new areas for the development of site-directed complement therapies, which can preserve mucosal barriers. The robust and versatile in vivo platforms established to investigate intestinal complement activity, its non-canonical function in the epithelium and canonical function in response to injury, and its regulation will also serve as a blueprint for developing therapies for other mucosal sites such as the lungs, urogenital tract and skin.


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 = $448,119 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$448,119
														Subtotal = $448,119

Grand Total All Awards = $448,119

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Canonical and non-canonical roles of the alternative pathway of complement in intestinal host defense

Award Number: DP2AI201039

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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