Abstract

In this grant proposal we focus on the function of a protein, CD2AP, which we have shown plays an important role in kidney glomerular function. This protein was originally cloned as a protein involved in T cell adhesion to antigen presenting cells. Surprisingly, CD2AP knockout mice die of nephrotic syndrome 6-7 weeks after birth. Its predominant expression in glomerular epithelial cells of the kidney and its ability to bind nephrin implicate CD2AP in the normal function of the slit diaphragm.
In specific aim number 1, we propose to determine the specific pattern of CD2AP expression in the kidney in greater detail.
In specific aim number 2, we propose to continue our analysis of homozygous and heterozygous CD2AP KO mice. We are particularly excited by our preliminary evidence suggesting that heterozygous CD2AP KO mice exhibit renal dysfunction. Lastly, in specific aim number 3, we propose to determine the function of CD2AP. Here we focus on defining the interaction of CD2AP with nephrin in greater detail and identifying protein partners for CD2AP. As glomerular epithelial specific genes are likely to play important roles in glomerular dysfunction, information from these studies are likely to lead to a better understanding of human renal disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058366-04
Application #
6608038
Study Section
General Medicine B Study Section (GMB)
Program Officer
Mullins, Christopher V
Project Start
2000-08-15
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
4
Fiscal Year
2003
Total Cost
$308,943
Indirect Cost

  Institution

Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Funk, Steven D; Lin, Meei-Hua; Miner, Jeffrey H (2018) Alport syndrome and Pierson syndrome: Diseases of the glomerular basement membrane. Matrix Biol 71-72:250-261
Fissell, William H; Miner, Jeffrey H (2018) What Is the Glomerular Ultrafiltration Barrier? J Am Soc Nephrol 29:2262-2264
Germino, Elizabeth A; Miller, Joseph P; Diehl, Lauri et al. (2018) Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer. PLoS One 13:e0194998
Luo, Wentian; Olaru, Florina; Miner, Jeffrey H et al. (2018) Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy. Front Immunol 9:1433
Brähler, Sebastian; Zinselmeyer, Bernd H; Raju, Saravanan et al. (2018) Opposing Roles of Dendritic Cell Subsets in Experimental GN. J Am Soc Nephrol 29:138-154
Eng, Diana G; Kaverina, Natalya V; Schneider, Remington R S et al. (2018) Detection of renin lineage cell transdifferentiation to podocytes in the kidney glomerulus with dual lineage tracing. Kidney Int 93:1240-1246
Tsuji, Kenji; Suleiman, Hani; Miner, Jeffrey H et al. (2017) Ultrastructural Characterization of the Glomerulopathy in Alport Mice by Helium Ion Scanning Microscopy (HIM). Sci Rep 7:11696
Tsuji, Kenji; P?unescu, Teodor G; Suleiman, Hani et al. (2017) Re-characterization of the Glomerulopathy in CD2AP Deficient Mice by High-Resolution Helium Ion Scanning Microscopy. Sci Rep 7:8321
Kim, Alfred Hj; Chung, Jun-Jae; Akilesh, Shreeram et al. (2017) B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2:
Malone, Andrew F; Funk, Steven D; Alhamad, Tarek et al. (2017) Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome. Pediatr Nephrol 32:997-1003

Showing the most recent 10 out of 31 publications