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Collaborative Studies on Lung Stem Cell Biology and Cell Based Therapy
 
 

Asrar B. Malik, Ph.D
University of Illinois College of Medicine at Chicago

Dr. Asrar Malik is the Head and Distinguished Professor of the Department of Pharmacology at the University of Illinois College of Medicine at Chicago. He received his Ph.D in Physiology from the University of Toronto.

Along with his position in the Department of Pharmacology at the University of Illinois College of Medicine at Chicago, he is also:

  • Director of the Center for Lung and Vascular Biology
  • Director of the Center for the Development of Stem Cell Therapies for Human Disease

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Consortium Research Title: Endothelial Progenitor Cell Treatment of Lung Vascular Injury

Consortium Research Description:

Development of cell-based treatment of Acute Lung Injury (ALI) poses multiple therapeutic challenges and pitfalls. The main features of ALI are impairment of oxygenation secondary to leaky lung microvessels and protein-rich edema. Injury of the endothelial cell (EC) barrier in pulmonary microvessels and resulting increased microvascular permeability to protein is the primary factor responsible for the pulmonary edema. Bone marrow (BM) -derived endothelial progenitor cells (EPCs) may afford an opportunity to prevent and/or reverse lung vascular injury and edemagenesis. However, the potential value of EPC treatment has not been systematically addressed and the mechanistic basis of EPC-mediated repair of the breeched endothelial barrier remains unclear. Our Supporting Data suggest the usefulness of EPC engraftment or EPC paracrine action in preventing sepsis induced-lung vascular injury and inflammation. However, little is known about the mechanisms of reconstitution of barrier function induced by EPCs. We will test the hypothesis that EPC engraftment and/or EPC paracrine effect prevents restores normal lung microvascular and resolves lung edema and inflammation by determining the (1) physiological outcomes of EPCs in sepsis-induced models of lung microvascular injury and edema formation and whether EPCs resolve lung edema and inflammation and promote survival; (2) the role of FoxM1 transcription factor in mediating EC proliferation and endothelial barrier regeneration induced by EPCs; (3) roles (a) of the sequential activation of EC RhoGTPase, RhoA, Rac1 and Cdc42, induced by EPCs and (b) of integrin alpha5beta1 expressed in EPCs in promoting EPC engraftment following lung microvascular injury; (4) role of lung inflammation versus resolved inflammation in the re-constitution of the barrier by EPCs; and (5) efficacy and safety of EPC treatment in large animal model of sepsis-induced lung microvascular injury and ALI. These studies will determine the mechanisms of improved survival and address the relevancy of a cell-based approach in ALI. It is hoped that the outcome of these studies will provide new information directly relevant to the therapeutic value of EPCs for the treatment in ALI.

 

Malik Lab Information:
The University of Illinois College of Medicine
835 S. Wolcott Ave.
Chicago, IL 60612
Phone: (312) 996-7635
Fax: (312) 996-1225

Assistant Name: Aileen F. Baker
Email Aileen
Phone: 312-996-7636

We are studying receptor-induced signaling pathways that regulate the barrier properties of endothelial and epithelial cells. These findings provide insights that are important to our understanding of normal and pathological conditions of the lung vasculature. A primary objective of the laboratory is to develop and test novel strategies for drug and gene delivery. We are interested in targeting cells specifically of the vessel wall which are critical elements involved in the pathogenesis of a variety of inflammatory diseases, including atherosclerosis, and of cancer metastasis. We are also studying the effects of exogenous endothelial progenitor cells on damaged endothelium. Finally, we are studying transcriptional regulation of the endothelial adhesion molecule ICAM-1 to develop strategies for controlling its expression and regulating detrimental leukocyte trafficking across the vascular endothelium.

 

Recent Publications

  • Zhao YY, Gao XP, Zhao YD, Mirza MK, Frey RS, Kalinichenko VV, Wang IC, Costa RH, Malik AB.  Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury. J Clin Invest. 116:2333-43, 2006.
  • Zhao YD, Ohkawara H, Rehman J, Wary KK, Vogel SM, Minshall RD, Zhao YY, Malik AB. Bone marrow progenitor cells induce endothelial adherens junction integrity by sphingosine-1-phosphate-mediated Rac1 and Cdc42 signaling. Circ Res. 105:696-704, 2009. NIHMS ID: 174477
  • Wary KK, Vogel SM, Garrean S, Zhao YD, Malik AB. Requirement of alpha(4)beta(1) and alpha(5)beta(1) integrin expression in bone-marrow-derived progenitor cells in preventing endotoxin-induced lung vascular injury and edema in mice. Stem Cells. 27:3112-20, 2009.
  • Zhao, Y.D., Ohkawara, H., Vogel, S.M., Malik, A.B., and Zhao, Y.Y. Bone marrow-derived progenitor cells prevent thrombin-induced increase in lung vascular permeability. Am J Physiol Lung Cell Mol Physiol 298:L36-44, 2010. PMCID: PMC2806201