AIF-1 在 VSMC 生长和动脉病变中的表达-猫眼课题宝

AIF-1 在 VSMC 生长和动脉病变中的表达

批准号：

7642563

负责人：

MICHAEL V AUTIERI

金额：

$32.77万

依托单位：

TEMPLE UNIV OF THE COMMONWEALTH

依托单位国家：

美国

项目类别：

财政年份：

2001

资助国家：

美国

项目状态：

已结题

起止时间：

2001-03-20 至 2011-06-30

来源：

https://reporter.nih.gov/project-details/7642563

关键词：

Actins Address Angioplasty Arterial Disorder Arterial Injury Binding Biological Assay Biology Blood Vessels Bone Marrow Cells Calcium-Binding Proteins Caliber Carotid Arteries Cells Clinical Clinical Markers Cytoskeletal Proteins Data Development Dominant-Negative Mutation Functional disorder Goals Granulocyte Colony-Stimulating Factor Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Human Hyperplasia Immune In Vitro Inflammation Inflammatory Injury Mediating Mediator of activation protein Molecular Molecular Profiling Pathway interactions Phenotype Play Proliferating Proteins Rattus Recruitment Activity Regulation Reporting Research Research Personnel Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Protein Site Small Interfering RNA Smooth Muscle Myocytes Testing Transgenic Mice Transplantation Tunica Adventitia Vascular Diseases allograft inflammatory factor-1 autocrine cell growth cytokine in vivo in vivo Model injured knock-down migration promoter protein protein interaction response response to injury scaffold tool transcription factor vascular smooth muscle cell proliferation

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DESCRIPTION (provided by applicant): As part of the VSMC response to injury, VSMC migrate into the lumen of the vessel where they proliferate and synthesize cytokines which they respond to in an autocrine fashion, sustaining the loss of lumen diameter. In the course of HL63810, we have determined that expression of Allograft Inflammatory Factor-1 (AIF-1), a newly described cytoplasmic, calcium-binding protein, is predictive of development of clinical transplant vasculopathy. Expression of AIF-1 in injured carotid artery significantly exacerbates reduction of lumen diameter and recruits bone marrow cells to the adventitia. Knock-down of AIF-1 abrogates neointimal hyperplasia. Expression of AIF-1 in human VSMC increases migration, proliferation, induces expression of G-CSF, and activates the Pad GTPase. AIF-1 contains several signaling domains, binds to and polymerizes actin, and activates signal transduction proteins. Our data support our central hypothesis that AIF-1 is an inflammation-responsive scaffold protein that plays a key role in regulation of VSMC activation and development of neointimal hyperplasia. The overall goals of this application are to 1- determine a cause and effect relationship between AIF-1 expression and neointimal hyperplasia in vivo, and 2- characterize the cellular pathways and molecular mechanisms responsible for AIF-1 activity in VSMC. Three aims have been formulated to test the hypothesis that; 1- AIF-1 expression exacerbates neointimal hyperplasia, and that reduction of AIF-1 expression will reduce neointimal hyperplasia in angioplasty-injured rats and AIF-1 transgenic mice, 2- that AIF-1 directly activates Rac1 signaling pathways leading to G-CSF expression, and that AIF-1 directly activates G-CSF expression with a subsequent autocrine activation of the Rac signaling pathway, and 3- AIF-1 activates Rac1 by activation of GEFs, and induces G-CSF expression by activation of transcription factors. Characterization of AIF-1 function will clarify our understanding of inflammation-mediated signal transduction leading to VSMC pathobiology and vascular- immune cell cross talk.

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