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Defining the Complosome in Human Cells, Tissues and Disease States

Award Number: R35GM136352
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/03/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Defining the Complosome in Human Cells, Tissues and Disease States - Abstract During the past three and one-half years of R01 grant support, we have made substantial progress in: a) assessing the role of C3 in the newly discovered intracellular complement system (ICS or “complosome”), including its modulation by CD46 signaling, b) developing an assay to quantitate a biologically active form of C3 known as C3(H2O), c) identifying a receptor-mediated C3(H2O) uptake process common to most cell types, and d) determining the ICS response in cells and an organ system (the airway) to ischemic and immune- mediated attack. Our immediate and ongoing goals are to publish our results describing the human receptor for C3(H2O) as well as studies demonstrating that C3 expression by lung transplants is reduced in alloimmune- mediated injury. We are also further delineating complosome activation and regulatory mechanisms at the RNA and protein level and are extending our analyses to human peripheral blood phagocytic, epithelial and, especially, endothelial cell populations. A further goal is to dissect the role of the ICS, utilizing both an in vitro model system with primary human cells isolated from lung tissue donors and corresponding human cell lines, as well as in mouse models of infection. Thus, we propose to continue to develop and employ model systems to obtain a detailed map of how a cell type's complosome functions in normal homeostasis as well as its response to cellular damage and malignancy. Such analyses will likely trigger new insights into how dysfunctions of this system correlate with human diseases. An important goal of this proposal relates to oncology. In addition to its role as an inhibitor of complement activation on host cells and a critical component of the complosome, CD46 is emerging as a key player in both malignant transformation and cancer immunotherapy. On one hand, CD46 is overexpressed on many tumors, yet on the other hand, it is targeted by therapeutic oncolytic viruses that use it as a docking mechanism. We have contributed to these studies and now plan to dissect the rationale of its overexpression and its effect on the complosome, beginning with multiple myeloma in collaboration with the Siteman Cancer Center. The models developed will be extended subsequently to other types of cancers. In summary, our proposal draws on the strength of our long-term commitment to the field of complement research and our ambitious undertakings related to defining the mechanisms and players of the newly discovered ICS. We are especially attracted to this grant mechanism because of its flexibility. This proposal draws not only on the expertise of the PI, but also on a team of talented individuals who are well positioned to continue being leaders the field by creating more innovative model systems and obtaining a comprehensive map that expands our knowledge-base relative to the “workings” of the ICS.


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 = -$88 )
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	11/5/2024	NON-COMPETING CONTINUATION	$0
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	001	5	8/5/2025	NON-COMPETING CONTINUATION	-$88
														Subtotal = -$88

Issue Date FY: 2024 ( Subtotal = $393,748 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	001	5	6/24/2024	NON-COMPETING CONTINUATION	$39,374
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	000	5	3/15/2024	NON-COMPETING CONTINUATION	$354,374
														Subtotal = $393,748

Issue Date FY: 2023 ( Subtotal = $393,748 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	8/29/2023	NON-COMPETING CONTINUATION	$393,748
														Subtotal = $393,748

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	001	3	7/6/2022	NON-COMPETING CONTINUATION	$39,377
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	3	3/28/2022	NON-COMPETING CONTINUATION	$354,373
														Subtotal = $393,750

Issue Date FY: 2021 ( Subtotal = $393,750 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	2	3/19/2021	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2020 ( Subtotal = $393,436 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	1	4/3/2020	NEW	$393,436
														Subtotal = $393,436

Grand Total All Awards = $1,968,344

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Defining the Complosome in Human Cells, Tissues and Disease States

Award Number: R35GM136352

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/03/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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