Medical Student Research Fellowship for Summer 2006

Mentor: Zhi-Ping Liu
Department: Internal Medicine
Room number: NB10.222
Mail Code: 79390-9148
Phone number: 214-648-1485
E-mail: liu@arnie.swmed.edu
Project title: role of Foxo4 in Atherosclerosis
Human subjects IRB approved project number (where applicable):
Animal subjects IRB approved project number (where applicable): 1068-05-0101
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Animal Based Basic Research

Brief Description of Project: Complications of atherosclerosis are the leading cause of mortality in developed countries. More than 100 genes that can influence atherogenesis have been identified. Our long-term goals are to elucidate the signaling dependent transcriptional mechanisms of these genes. Recently, we identified a novel transcriptional mechanism by which FOXO4 regulates smooth muscle cell (SMC) phenotypes and transcription of matrix metalloproteinase 9 (MMP9) and Toll-like-receptor 4 (TLR4). As SMC phenotypic modulation, MMP9, and TLR4 are involved in atherogenesis, we hypotheize that FOXO4 contributes to atherosclerosis through these effectors. Three specific research projects are being performed in the lab. (1) To characterize the signaling pathways that regulate FOXO4 activities. We are investigating whether FOXO4 mediates JNK-activated MMP9 transcription and whether JAK/STAT signaling suppresses MMP9 transcription through inactivation of FOXO4 by PIM kinases. (2) To investigate the role of FOXO4 in transcriptional activation of TLR4. We are studying the molecular mechanism by which FOXO4 activates TLR transcription and examine whether upregulation of TLR4 by FOXO4 is sufficient to promote TLR4-mediated proinflammatory cytokine production. We are also investigating whether FOXO4 plays a role during monocyte to macrophage differentiation. (3) To determine whether and how FOXO4 promotes atherosclerosis. We are testing whether inactivation of Foxo4 in apoE-null mice reduces atherosclerosis and whether Foxo4 influences atherosclerosis through downstream effectors (TLR4, MMP9), and/or SMC phenotypic modulation. The lack of response to lipid-lowering drugs in patients with cardiovascular disease emphasizes the need to identify new therapeutic targets for the treatment of atherosclerosis. FOXO4 is a promising target for therapeutic intervention since inhibition of FOXO4 activity may reduce TLR4-induced cytokine production, reduce intimal thickening, and stabilize late atherosclerotic plaques.

Previous Research Activities or Publications with Medical Students: N/A

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