The receptor for the globular heads of C1q, gC1q-R/p33, is a ubiquitously expressed cellular protein and comprises of three identical chains of -33 kDa. Although the primary destination is the mitochondria, it has a multi-compartmental distribution including its expression on the cell surface of endothelial cells and platelets. It is the cell -surface function that is the focus of this proposal. gC1q-R was initially identified as a receptor for C1q, but we have also shown binding to other biologically important ligands including high molecular weight kininogen (HK) and factor XII (FXII). Substantial experimental evidence supports the concept that gC1q-R plays an important role in the inflammatory process especially at sites of vascular injury where gC1 q-R expressing endothelial cells, platelets and macrophages are at the center of the process. The present proposal is designed to dissect the structure-function relationships of gC1q-R by focusing primarily on its binding to the cell surface and three of its specific ligands ?C1q, HK and FXII. These ligands are not only critical in the initiation of the classical pathway of complement and contact activation;we propose they also play a major role at sites of inflammation by directly or indirectly enhancing the inflammatory process. The key aims are: 1) analysis of the role of structural domains of the molecule in its binding to cell surfaces and to major physiological ligands;2) its role in inflammation, by assessing its regulatory and/or initiatory functions on the complement and contact activation systems (e.g. generation of potent vasoactive peptides like bradykinin);and 3) its role as a signaling agent in response to C1q, and perhaps other ligands, in endothelial cells, leading to generation of proinflammatory molecules. Understanding the function of gC1q-R is of biologic importance because it is a novel regulatory protein involved not only in the complement and kinin-generating systems, but also possibly the acquired or adaptive immune systems as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060866-04
Application #
7568971
Study Section
Special Emphasis Panel (ZRG1-III-F (01))
Program Officer
Sawyer, Richard T
Project Start
2006-03-01
Project End
2012-02-28
Budget Start
2009-03-01
Budget End
2012-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$295,291
Indirect Cost
Name
State University New York Stony Brook
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Ghebrehiwet, Berhane; Kandov, Evelyn; Kishore, Uday et al. (2018) Is the A-Chain the Engine That Drives the Diversity of C1q Functions? Revisiting Its Unique Structure. Front Immunol 9:162
Ghebrehiwet, Berhane; Hosszu, Kinga H; Peerschke, Ellinor I B (2017) C1q as an autocrine and paracrine regulator of cellular functions. Mol Immunol 84:26-33
Pednekar, Lina; Valentino, Alisa; Ji, Yan et al. (2016) Identification of the gC1qR sites for the HIV-1 viral envelope protein gp41 and the HCV core protein: Implications in viral-specific pathogenesis and therapy. Mol Immunol 74:18-26
Ghebrehiwet, Berhane; Kaplan, Allen P; Joseph, Kusumam et al. (2016) The complement and contact activation systems: partnership in pathogenesis beyond angioedema. Immunol Rev 274:281-289
Peerschke, Ellinor Ib; Brandwijk, Ricardo Jmge; Dembitzer, Francine R et al. (2015) Soluble gC1qR in Blood and Body Fluids: Examination in a Pancreatic Cancer Patient Cohort. Int J Cancer Res Mol Mech 1:
Ramadass, Mahalakshmi; Ghebrehiwet, Berhane; Kew, Richard R (2015) Enhanced recognition of plasma proteins in a non-native state by complement C3b. A possible clearance mechanism for damaged proteins in blood. Mol Immunol 64:55-62
Ramadass, Mahalakshmi; Ghebrehiwet, Berhane; Smith, Richard J et al. (2014) Generation of multiple fluid-phase C3b:plasma protein complexes during complement activation: possible implications in C3 glomerulopathies. J Immunol 192:1220-30
Peerschke, Ellinor I B; Ghebrehiwet, Berhane (2014) cC1qR/CR and gC1qR/p33: observations in cancer. Mol Immunol 61:100-9
Bossi, Fleur; Tripodo, Claudio; Rizzi, Lucia et al. (2014) C1q as a unique player in angiogenesis with therapeutic implication in wound healing. Proc Natl Acad Sci U S A 111:4209-14
Ghebrehiwet, Berhane; Peerschke, Ellinor I B (2014) Purification of C1q receptors and functional analysis. Methods Mol Biol 1100:319-27

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