Michael Autieri PhD

From Legacyview Dictionary of Biography

Associate Professor, Physiology, Department of Physiology, Cardiovascular Research Center, Temple University

Educational Background:

   PhD, Hahnemann University, Philadelphia, PA

Research Interests:

The broad focus of my research program is the identification and characterization of proteins that play a role in progression of neointimal hyperplasia subsequent to arterial injury, including proliferative, inflammatory, and anti-inflammatory proteins. Our specific goal is to understand the molecular mechanisms of vascular smooth muscle cell activation leading to neointimal hyperplasia. We have two major areas of investigation currently NIH- funded or pending NIH funding. One is AIF-1, which is a pro-inflammatory signal transduction protein, and the other is IL-19, an anti-inflammatory, vasculoprotective cytokine.

Title: The role of Allograft Inflammatory Factor-1 in VSMC activation and vascular restenosis. We have identified a protein termed Allograft Inflammatory Factor-1 (AIF-1), which is a cytoplasmic, calcium-binding protein. We have determined that AIF-1 expression 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 Rac1 GTPase. AIF-1 contains several signaling domains, binds to and polymerizes actin, and interacts with signaling 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. Our immediate goals 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. We currently utilize an AIF-1 VSMC specific transgenic mouse, in tandem with ex vivo molecular and cellular biological analysis for many of our studies. We have taken this project from an unidentified band on a differential display gel through identification of a novel gene to cellular and molecular characterization up to generation of a transgenic and pending conditional knock out mouse. Characterization of AIF-1 function will clarify our understanding of inflammation-mediated signal transduction leading to VSMC pathobiology and vascular-immune cell cross talk.

Title: Expression and direct suppressive effects of anti-inflammatory cytokines on VSMC and vascular restenosis. Our overall hypothesis is that IL-19 plays a protective role in the vascular response to injury by at least one of two processes: 1- direct inhibitory effects on VSMC activation, and 2- attenuation of the inflammatory response. IL-19 is a recently described member of the IL-10 family of anti-inflammatory cytokines. IL-19 expression is ascribed to be restricted to hematopoetic and inflammatory cells, where it has an anti-inflammatory effect. Nothing has been reported on the mechanism(s) of IL-19 effects, either in immune or vascular cells. We have preliminary data showing; IL-19 is not expressed in quiescent vascular smooth muscle cells (VSMC) or normal arteries, but is induced in VSMC by inflammatory cytokines and in arteries by injury; IL-19 is anti-proliferative for cultured, human coronary artery VSMC, and induces phosphorylation of STAT-3 in these cells; IL-19 pre-treatment inhibits inflammation-stimulated activation of ERK1/2 and p38; inhibits inflammation-stimulated expression of proliferative and inflammatory genes including, but not limited to, IL-8, COX2, CRP, ICAM-1, cyclins, and c-fos; induces expression of the suppressor of cytokine signaling 5 (SOCS5), but inhibits expression and translocation of HuR, a transcription factor which regulates stability of inflammatory and proliferative gene mRNA. IL-19 adenoviral gene transfer significantly reduces neointimal formation in balloon angioplasty-injured rat carotid arteries. Although a great deal of attention has been given to the role and effects of pro inflammatory cytokines, little has been reported on the potential protective effects of anti-inflammatory cytokines on the vascular response to injury with respect to direct effects on VSMC pathophysiology. The overall goals of this project are designed to characterize the mechanism of IL-19 suppressive effects on VSMC and development of intimal hyperplasia; and define a role for IL-19 in vascular-immune cell communication. We propose that IL-19 is a novel factor central to both of these processes.