Acute renal failure (ARF) is a serious medical problem that occurs in 5% of all hospitalized patients. The prognosis of ARF is poor and has remained unchanged over the past three decades carrying a high mortality rate of about 50%. Although ARF is the result of many causes, the most common cause is injury to the renal tubular epithelial cells (RTEC). These cells, once injured, die by necrosis or apoptosis depending on the nature and severity of the insult. Severe injury usually triggers necrosis whereas milder insults to the kidney cause apoptotic death of the RTEC. Necrosis is difficult to prevent, whereas apoptosis can potentially be modulated to maintain cell viability. Therefore, identifying the different components of the apoptotic pathway, especially the ones that play a major role in kidney, can help us understand renal injury-induced apoptosis. These new components can also provide specific and novel targets for intervention to help patients with acute renal failure. Our studies are focused on a recently isolated and characterized pro-apoptotic protease Omi, also known as HtrA2, and its role in renal injury. This protein is present in the mitochondria and is released to the cytoplasm upon induction of apoptosis. In this capacity, Omi is unique both in its structure as well as its function. In the cytoplasm, Omi can induce apoptosis through a caspase-dependent as well as in a caspase-independent pathway. It is the aim of this proposal to investigate the potential role of Omi in the apoptotic cell death that occurs in RTEC. Our studies will investigate the involvement of Omi in renal injury and the molecular events that follow its activation leading to apoptosis. Furthermore, by blocking the proteolytic activity of Omi using a specific inhibitor, a new approach to potentially protect and maintain cell viability will be tested. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055734-08
Application #
7157585
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2005-03-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
8
Fiscal Year
2007
Total Cost
$271,854
Indirect Cost
Name
University of Central Florida
Department
Type
Organized Research Units
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
Cilenti, Lucia; Balakrishnan, Meenakshi P; Wang, Xiao-Liang et al. (2011) Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination. J Mol Cell Cardiol 50:652-61
Balakrishnan, Meenakshi P; Cilenti, Lucia; Ambivero, Camilla et al. (2011) THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death. Biochem Biophys Res Commun 404:195-200
Kim, Jinu; Kim, Dong Sun; Park, Mae Ja et al. (2010) Omi/HtrA2 protease is associated with tubular cell apoptosis and fibrosis induced by unilateral ureteral obstruction. Am J Physiol Renal Physiol 298:F1332-40
Balakrishnan, Meenakshi P; Cilenti, Lucia; Mashak, Zineb et al. (2009) THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death. Am J Physiol Heart Circ Physiol 297:H643-53
Cilenti, Lucia; Kyriazis, George A; Soundarapandian, Mangala M et al. (2005) Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells. Am J Physiol Renal Physiol 288:F371-9
Cilenti, Lucia; Soundarapandian, Mangala M; Kyriazis, George A et al. (2004) Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. J Biol Chem 279:50295-301
Cilenti, Lucia; Lee, Younghee; Hess, Sibylle et al. (2003) Characterization of a novel and specific inhibitor for the pro-apoptotic protease Omi/HtrA2. J Biol Chem 278:11489-94
Junqueira, Daniela; Cilenti, Lucia; Musumeci, Lucia et al. (2003) Random mutagenesis of PDZ(Omi) domain and selection of mutants that specifically bind the Myc proto-oncogene and induce apoptosis. Oncogene 22:2772-81
Faccio, L; Fusco, C; Viel, A et al. (2000) Tissue-specific splicing of Omi stress-regulated endoprotease leads to an inactive protease with a modified PDZ motif. Genomics 68:343-7
Faccio, L; Fusco, C; Chen, A et al. (2000) Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J Biol Chem 275:2581-8

Showing the most recent 10 out of 11 publications