Martin S Kluger, PhD

Research Scientist in Immunobiology

Research Interests

Edema; Permeability; NF-kappa B; Sepsis; Tight Junctions; Adherens Junctions; Tumor Necrosis Factor Decoy Receptors; Microvessels

Research Organizations

Vascular Biology and Therapeutics Program

Research Summary

Endothelial cells form an inner lining to human microvessels that serve as a systemic organ for regulating the access of fluid, macromolecules and cells from circulating blood into all vascularized tissues. We focus on how to maintain stable endothelial cell-cell junctions during activation by inflammatory mediators (cytokines). This is important to systemic sepsis, atherosclerosis and ischemia reperfusion injury. We are also interested in how endothelial cells and pericytes form new microvessels (angiogenesis). This process is relevant to wound healing, to tumor (lymph)angiogenesis and to the engineering of vascularized synthetic tissues.

Extensive Research Description

We are defining how the inflammatory cytokine tumor necrosis factor (TNF) destabilizes blood vessel barrier integrity by increasing their paracellular permeability to fluid and (macro)molecules in circulating blood. We study how transmembrane adhesion molecules found at cell-cell junctions (such as claudin-5, JAM-A, occludin and VE-cadherin) regulate paracellular permeability by knocking down and overexpressing these genes in cultured primary human endothelial cells (EC). A second research goal with applications to biomedical engineering of replacement organs is in defining how nascent microvessels become stabilized when EC interact with accessory cells (pericytes) during angiogenesis. In this work, we explore the molecular mechanisms of microvascular tube formation by EC and pericytes in 3-D collagen/fibronectin matrices.

1. In RO1 grant-supported research funded by he NIH-NHLBI (Proteins of the Endothelial Cell Surface 2R01HL036003, Kluger, MS and Pober, J.S co-Principal Investigators) we focus on the role of tight junction (TJ) proteins, especially claudin 5, in human capillary ECs, and how TJs (and claudin 5) are affected by the pro-inflammatory cytokine, tumor necrosis factor (TNF). Our specific aims are first, to characterize the organization of TJs, with emphasis on the role of claudin 5, in human continuous capillary ECs and determine how TJ proteins interact with each other and with the actin cytoskeleton. Second, to determine how TNF affects the organization of human capillary TJ proteins and identify those proteins whose expression levels are changed by TNF, resulting in TJ disruption and capillary leak. Third, to determine how KLF4 regulates TNF-induced changes in capillary ECs and if this can be exploited to control TNF-induced pathological changes.

2. In other NIH-NHLBI-funded research (Optimizing Revascularization by Endothelial Cell Transplantation RO1-HL085416, Saltzman, W.M. and Pober, J.S. Co-PIs; Kluger, M.S., Co-Investigator) we introduce into SCID-beige immunodeficient mice human EC of wild type and mutant forms of Bcl-2, TNF-R2 and Etk for revascularization within scaffolds; we optimize the conditions for transplantation of transduced EC by incorporation of wild type or modified human pericytes (or vascular smooth muscle cells), by modifications of the scaffold composition; we also introduce controlled release of agents into the scaffold design such as a inhibitory microRNA aimed at modulating cord formation by EC and pericytes/SMCs.

Selected Publications

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Contact Info

Martin S Kluger, PhD

Curriculum Vitae