Cytosolic phospholipase A2 interacts with 3 proteins, including Tip60, a Tip60 splice variant which we have called PLIP, and SIRT2. The goals of this grant have been to study the molecular basis for and roles of these proteins in mesangial cell apoptosis. Tip60 and PLIP are acetyltransferase proteins that enhance cell susceptibility to apoptosis. PLIP's proapoptotic effect is associated with a cPLA2-dependent increase in PGE2 generation. We have recently demonstrated that PLIP expression is also associated with a striking decrease in pRb levels and a decrease in the percentage of cells in GO/G1 accompanied by an increase in subG. This data suggests that PLIP and cPLA2 may function at the G2/M checkpoint and induce G2/M arrest or apoptosis following DNA damage. Using a Tip60-specific antibody, we have shown that Tip60 and PLIP localize to different cellular compartments of mesangial cells, suggesting that they may not share identical functions. SIRT2 shares large areas of homology with other class I sirtuins, including SIRT1. Although little is known about SIRT2, SIRT1 has been associated with p53 activity and with apoptosis. We have identified the binding site between cPLA2 and SIRT2 and show that it is contained within a highly conserved region. Our hypothesis is that cPLA2, via its interaction with PLIP and/or Tip6O and with SIRT2 modulates apoptosis following DNA damage. This proposal includes 3 specific aims: 1) To elucidate the mechanisms underlying the localization of Tip60, PLIP and SIRT2 and their interaction to cPLA2;2) To determine the effects of these proteins on cell cycle regulation and whether these effects are functionally related to their interaction with cPLA2 and on cPLA2-dependent arachidonic acid release and PGE2 generation;and 3) To determine and elucidate the role of Tip60, PLIP, SIRT2 and cPLA2 in regulation of apoptosis following DNA damage. We will use basic methods of molecular biology and cellular biochemistry to answer these questions. The regulation of cell cycle events and apoptosis in the mesangial cell is critical in the progression or resolution of glomerulonephritides, including diabetic nephropathy. A better understanding of these events may allow us to develop therapies to better treat these incapacitating and costly diseases and thus limit the need for renal replacement therapy. Given the large number of patients that are initiated on dialysis each year, this addresses a critical public health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054741-09
Application #
7797673
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Mullins, Christopher V
Project Start
1999-08-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$337,965
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Liu, Nai-Kui; Deng, Ling-Xiao; Zhang, Yi Ping et al. (2014) Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury. Ann Neurol 75:644-58
Suram, Saritha; Silveira, Lori J; Mahaffey, Spencer et al. (2013) Cytosolic phospholipase A(2)? and eicosanoids regulate expression of genes in macrophages involved in host defense and inflammation. PLoS One 8:e69002
Bonventre, Joseph V (2012) Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol 32:452-62
Krolewski, Andrzej S; Bonventre, Joseph V (2012) High risk of ESRD in type 1 diabetes: new strategies are needed to retard progressive renal function decline. Semin Nephrol 32:407-14
Bonventre, Joseph V (2012) Limb ischemia protects against contrast-induced nephropathy. Circulation 126:384-7
Kerkelä, Risto; Boucher, Matthieu; Zaka, Raihana et al. (2011) Cytosolic phospholipase A(2)? protects against ischemia/reperfusion injury in the heart. Clin Transl Sci 4:236-42
Yang, Li; Humphreys, Benjamin D; Bonventre, Joseph V (2011) Pathophysiology of acute kidney injury to chronic kidney disease: maladaptive repair. Contrib Nephrol 174:149-55
Kurusu, Shiro; Sapirstein, Adam; Sawada, Harumi et al. (2011) Group IVA phospholipase A2 regulates testosterone biosynthesis by murine Leydig cells and is required for timely sexual maturation. Biochem J 439:403-11
Parti, Rajinder P; Loper, Robyn; Brown, Gordon D et al. (2010) Cytosolic phospholipase a2 activation by Candida albicans in alveolar macrophages: role of dectin-1. Am J Respir Cell Mol Biol 42:415-23

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