Microtubule-associated regulation of acute lung injury

University Of Chicago, Chicago IL

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Abstract

? DESCRIPTION (provided by applicant): Lung inflammation and alterations in endothelial cell (EC) permeability play a major role in the pathophysiology of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the conditions associated with high mortality rates. Low efficiency of current therapies may be explained in part by focus on drug treatments aimed at prevention of the onset of ALI, while endogenous feedback mechanisms which subside inflammatory activation and EC barrier dysfunction, although much more clinically relevant, remain poorly understood. Our studies in the previous cycle identified a novel role of microtubule (MT) peripheral network in the control of lung EC barrier function. We discovered that stimulation of MT peripheral growth by barrier enhancing agonists, such as hepatocyte growth factor, promoted Rac GTPase-dependent and attenuated Rho GTPase-dependent signaling, thus leading to downregulation of vascular leak. We defined a novel paradigm of dual regulation of Rac and Rho pathways by MT-associated guanine nucleotide exchange factors Asef and GEF-H1 and demonstrated essential role of MT in the mechanisms of Rac-Rho crosstalk and control of endothelial permeability. However, the entire mechanism of MT-dependent regulation of onset and resolution of ALI, and specifically, MT-dependent modulation of inflammatory cascades, remains poorly understood. During the screening of potential signaling proteins associated with MT in control and inflamed pulmonary EC we discovered association of Suppressor Of Cytokine Signaling, SOCS1, with the MT fraction. This serendipity finding suggested a novel link of MT cytoskeleton to the control of endothelial inflammatory activation and changes in permeability associated with EC inflammatory response. The role of MT in the modulation of EC response to bacterial wall compounds, cytokines, etc., remains virtually unknown. We hypothesize that that cellular feedback mechanisms modulating inflammatory response critically require MT- assisted SOCS1 targeting to the submembrane compartment, where it interacts with its cytokine receptor- and TLR-associated protein targets. This hypothesis will be tested in four Specific Aims. Aim-1 will characterize regulation of LPS-induced inflammation by SOCS1 in cell, ex vivo and in vivo models of LPS-induced ALI. Aim- 2 will investigate involvement of microtubules in control of SOCS1 anti-inflammatory function. Aims 3 and 4 will identify molecular mechanisms of MT-assisted SOCS1 intracellular targeting. Aim-3 will examine the role of MT motors in SOCS1 delivery to the cell periphery. Aim-4 will investigate the role MT plus-end proteins in SOCS1 anchoring at the cell periphery. The results of this project will delineate novel MT-dependent mechanisms regulating lung barrier dysfunction and inflammation, which may lead to discovery of a new group of pharmacological molecules for the treatment of ALI/ARDS.