Dr. Fujise's long-term objectives is to serve as a molecular biologist and cardiologist, whose main focus is prevention and treatment of cardiovascular diseases using molecular biological approach. Under the guidance and direction of Dr. Edward T.H. Yeh, Dr. Fujise has performed the research in the field of apoptosis regulation. In the process of characterizing MCL1(ML1 myeloid cell leukemia), a Bcl-2 homologue, Dr. Fujise discovered a novel interaction between MCL1 and PCNA (Proliferating cell nuclear antigen). PCNA is a 29kDa nuclear protein involved in DNA repair and replication and cell proliferation and differentiation. The role of PCNA has been implicated in pathogenesis of SLE (Systemic lupus erythematosis), restenosis after angioplasty and others. Apoptosis as well as the lack of it play critical roles in many human diseases including cancer, AIDS, myocarditis, atherosclerosis and myocardial infarction. The MCL1-PCNA interaction may be an important molecular link between anti-apoptotic proteins and cell cycle proteins. Based on the hypothesis that MCL1 plays a role in DNA repair and replication and cell proliferation and differentiation through its interaction with PCNA, Dr. Fujise here proposes to characterize the MCL1-PCNA interaction over the five years of the Award. First, Dr. Fujise will further characterize biochemical aspects of MCL1-PCNA interaction, using yeast two hybrid system. Second, Dr. Fujise will investigate the functional significance of the MCL1-PCNA interaction, including the effect of MCL1 over- expression on cell proliferation and the effect of MCL1 on DNA polymerase delta, DNA methylase, and DNA repair enzymes in the presence of PCNA. Finally, the impact of cell cycle phases, phosphorylation and DNA damage on MCL1-PCNA interaction and MCL1's subcellular localization will be evaluated. With Dr. Yeh as his Mentor, Dr. Fujise will perform his research at Research Center for Cardiovascular Diseases within the Institute of Molecular Medicine for Prevention of Human Diseases, devoting 80 percent of his professional time to the research. The Research Center and Institute will provide Dr. Fujise with a highly interactive and productive environment as well as with all the equipment needed for his research. The Scientific Advisory Committee, consisting of three senior scientists including the mentor will guide Dr. Fujise's scientific progress. At the completion of this Award, Dr. Fujise will be an independent, highly productive investigator with a high likelihood of making critical contributions in the fieled of apoptosis regulations and in prevention and treatment of cardiac diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL004015-03
Application #
6388531
Study Section
Special Emphasis Panel (ZHL1-CSR-K (F2))
Program Officer
Commarato, Michael
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$124,686
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Koide, Yuichi; Kiyota, Tomomi; Tonganunt, Moltira et al. (2009) Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation. Biochim Biophys Acta 1790:326-38
Pinkaew, Decha; Cho, Sung Gook; Hui, David Y et al. (2009) Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration. Biochim Biophys Acta 1790:31-9
Mnjoyan, Zakar H; Doan, Dennis; Brandon, Jimi Lynn et al. (2008) The critical role of the intrinsic VSMC proliferation and death programs in injury-induced neointimal hyperplasia. Am J Physiol Heart Circ Physiol 294:H2276-84
Graidist, Potchanapond; Yazawa, Michio; Tonganunt, Moltira et al. (2007) Fortilin binds Ca2+ and blocks Ca2+-dependent apoptosis in vivo. Biochem J 408:181-91
Graidist, Potchanapond; Phongdara, Amornrat; Fujise, Ken (2004) Antiapoptotic protein partners fortilin and MCL1 independently protect cells from 5-fluorouracil-induced cytotoxicity. J Biol Chem 279:40868-75
Mnjoyan, Zakar H; Dutta, Ranjan; Zhang, Di et al. (2003) Paradoxical upregulation of tumor suppressor protein p53 in serum-stimulated vascular smooth muscle cells: a novel negative-feedback regulatory mechanism. Circulation 108:464-71
Mnjoyan, Zakar H; Fujise, Ken (2003) Profound negative regulatory effects by resveratrol on vascular smooth muscle cells: a role of p53-p21(WAF1/CIP1) pathway. Biochem Biophys Res Commun 311:546-52
Tulis, David A; Mnjoyan, Zakar H; Schiesser, Rachel L et al. (2003) Adenoviral gene transfer of fortilin attenuates neointima formation through suppression of vascular smooth muscle cell proliferation and migration. Circulation 107:98-105
Zhang, Di; Li, Franklin; Weidner, Douglas et al. (2002) Physical and functional interaction between myeloid cell leukemia 1 protein (MCL1) and Fortilin. The potential role of MCL1 as a fortilin chaperone. J Biol Chem 277:37430-8
Li, F; Zhang, D; Fujise, K (2001) Characterization of fortilin, a novel antiapoptotic protein. J Biol Chem 276:47542-9

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