Thursday, December 26, 2024
12/26/2024
The complement system plays an important role in a diverse spectrum of kidney diseases, including autoimmune glomerulonephritis as well as many conditions not traditionally thought of as immune-mediated. Factor H (FH) is a centrally important complement protein in the blood that serves as a major regulator of complement activation in both the fluid phase as well as on cell surfaces and interstitial matrices. Factor H- related proteins (FHRs) comprise a structurally related family of five genes in humans which have recently been identified as key pathogenic drivers of human kidney diseases by acting as modulators of complement and/or FH function. However, the functions of the FHRs are complex and controversial. In addition, animal models of individual FHR deficiency and FHR protein-specific monoclonal antibodies (mAbs) were not previously available for evaluating the in vivo roles of these proteins. Our proposal addresses this important knowledge gap. The overall hypothesis of this project is that individual FHRs competitively antagonize or otherwise modulate FH function and complement activation on specific surfaces in the kidney, and this has a profound effect on complement-mediated inflammation at these sites. Furthermore, by interfering with C3d- receptor interactions, the FHRs also have a strong effect on the upstream immune response to self and foreign antigens. To test this hypothesis we propose the following specific aims. Aim 1. Examine the functions of the different FHRs on distinct kidney surfaces. We have developed a “toolbox” for studying the FHRs in the kidney, including mice with targeted deletion of the individual FHRs, recombinant forms of the FHRs, and monoclonal antibodies to the FHRs. We will use these tools to map the interactions of the FHRs with healthy and diseased kidneys. Aim 2. Examine the roles of individual murine FHRs in the development of autoimmunity. We will use panel of FHR deficient mice to study the effects of these proteins on the development of antibodies to self and foreign antigens. Aim 3. Examine the role of the FHRs as downstream mediators of kidney inflammation. We will use FHR-deficient mice and recombinant FHR proteins to examine the role of the FHRs in causing complement dysregulation in glomerular and tubulointerstitial diseases. The studies in this proposal are innovative, because they utilize novel reagents and approaches to examine the function of the FHRs. This project is significant, because will improve our understanding of a family of proteins that are poorly understood but that have been linked with several different diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).