Martin S Kluger, PhD

Research Scientist in Immunobiology

Research Interests

Edema; Immune System; Permeability; NF-kappa B; Sepsis; Tight Junctions; Adherens Junctions; Microvessels

Public Health Interests

Cardiovascular Disease; Sepsis

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.

Specialized Terms: Sepsis; Vascular Hyperpermeability (leak); Tumor Necrosis Factor (TNF); Interleukin-1 (IL-1); Claudin-5; Microvascular Endothelial Cells; NF-κB signaling

Extensive Research Description

Vascular hyper-permeability (or “leak”) is a life threatening consequence of systemic inflammatory disease in bacterial sepsis, in viral hemorrhagic disease or in pathogenic-free immune responses such as SIRS. A better understanding of endothelial cell inflammation is needed for developing effective therapies that may prevent the loss of selective permeability, an important feature of the healthy microvascular endothelium present in bodily organs. We are currently using system based approaches like RNA-Seq and siRNA library screening to identify new molecular targets and to define gene expression patterns by which the inflammatory cytokine tumor necrosis factor (TNF) destabilizes blood vessel barriers. This work employs our in vitro model of tight junction-dependent endothelial barrier function, which models how capillary leak leads to organ failure in inflammatory disease.

In a pilot project award to Martin S. Kluger funded by the Yale Center for Molecular Discovery we have performed a phenotypic screen in cultured microvascular endothelial cells of the entire human kinome to identify kinases regulating TNF leak. We are now characterizing these results, which may form the basis of novel therapeutic targets. We anticipate this approach, performed in collaboration with the inventors of ECIS at Applied BioPhysics, Inc. (Troy, NY) will be applicable to ECIS-based high throughput functional screening of diverse adherent cell types using different inflammatory mediators, e.g., other cytokines, PAMPs, DAMPs or toxins, or by replacing siRNA with CRISPR (by methods reported in our publication Abrahimi, et al., Efficient gene disruption in cultured primary human endothelial cells by CRISPR/Cas9. 2015. Circulation Research. 117: 121-128).

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 have focused on how inflammatory cytokines such as TNF, IL-1b and LPS act on tight junction (TJ) proteins because of their essential role in the permeability barriers of capillaries, which form the largest anatomical interface separating blood from vascularized organs and are the microvascular segment most responsible for preventing harmful hyperpermeability responses. In this work we have characterized signaling pathways affecting the organization of TJs in human microvascular endothelial cells, with an emphasis on the role of claudin-5, and have studied how TJ proteins interact with the actin cytoskeleton.

Selected Publications

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Contact Info

Martin S Kluger, PhD

Curriculum Vitae

Research Image 1

Tight Junction Disassembly in Inflammation