As a result of work during the first cycle of this grant, we realize that CD47 or integrin-associated protein can modulate the function of a number of vascular integrins through its direct activation of heterotrimeric Gi. Much less is known about CD47 function in the immune system. We have found that CD47 and its counter receptor SIRPalpha constitute a novel recognition of self system that prevents phagocytosis of CD47-bearing circulating cells. Failure of this system leads to autoimmune syndromes. All ligands of CD47 (thrombospondin, monoclonal antibodies and SIRPalpha can induce a novel form of cell death in activated lymphocytes, i.e., Jurkats and anti-CD3 activated normal T cells. The mechanism involves heterotrimeric G proteins and attenuation of PKA activity leading to a loss of delta-psi-m. We find that CD47 null mice have a severe defect in IgM to IgG class switching. Here we propose to investigate the mechanisms behind these newly revealed functions of CD47 in the immune system.
The aims are: 1. Determine the biological role and mechanism of the CD47-SIRPalpha inhibition of phagocytosis of circulating cells. This normally attenuates presentation of self antigens and its mechanism suggests a novel treatment for autoimmune hemolytic anemia. 2. Investigate the mechanism of CD47 mediated cell death, particularly the connection from G proteins to mitochondrial damage. 3. Use CD47 null mice to define the role of CD47 in development of immune cells, in class switching during an immune response and in autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM057573-07S1
Application #
6917763
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Somers, Scott D
Project Start
1998-05-01
Project End
2007-04-30
Budget Start
2004-07-10
Budget End
2005-04-30
Support Year
7
Fiscal Year
2004
Total Cost
$57,375
Indirect Cost
Name
Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Isenberg, Jeff S; Qin, Yan; Maxhimer, Justin B et al. (2009) Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress. Matrix Biol 28:110-9
Isenberg, Jeff S; Roberts, David D; Frazier, William A (2008) CD47: a new target in cardiovascular therapy. Arterioscler Thromb Vasc Biol 28:615-21
Isenberg, Jeff S; Romeo, Martin J; Maxhimer, Justin B et al. (2008) Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model: implications for human disease. Ann Surg 247:860-8
Wang, Hui; Madariaga, Maria Lucia; Wang, Shumei et al. (2007) Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells. Proc Natl Acad Sci U S A 104:13744-9
Blazar, B R; Lindberg, F P; Ingulli, E et al. (2001) CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells. J Exp Med 194:541-9
Capo, C; Lindberg, F P; Meconi, S et al. (1999) Subversion of monocyte functions by coxiella burnetii: impairment of the cross-talk between alphavbeta3 integrin and CR3. J Immunol 163:6078-85
Pettersen, R D; Hestdal, K; Olafsen, M K et al. (1999) CD47 signals T cell death. J Immunol 162:7031-40