Despite recent advances in understanding of the many aspects of the pathogenesis of acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS), there are currently no effective pharmacological or cell-based treatments for the disease. Employing novel animal models and integrated pharmacological and molecular and cellular biological approaches, the focus of Project 3 in the context of the Program Project will be to define for the first time the reprogramming of lung macrophages (M?) to the M2 lineage as regulated by the interaction of endothelial cell (EC)-expressed Jagged1 (Jag1, a Notch ligand) with M?- expressed Notch. We will determine whether these ?instructed? cells have the potential to resolve inflammatory lung injury. We hope through these studies to develop novel therapeutics to promote resolution of inflammatory lung injury and enhance lung?s tolerance to injury. Our Supporting Data show that disruption of Jag1 in EC induces reprogramming of M? towards the M2-like anti-inflammatory phenotype and resolution of lung inflammation. Thus, in Project 3, we will test the hypothesis that the interaction of M? with lung EC-expressed Jag1 mediates Notch signaling in M? and thereby determines their polarity and their ability to resolve inflammatory lung injury. The proposed studies will address the following Specific Aims.
In Aim 1, we will determine the regulation of polarization of M? by EC-expressed Jag1 and its role in resolving inflammatory lung injury and promoting tolerance to injury induced by secondary infection.
In Aim 2, we will define the signaling mechanisms activated in M? that mediate EC Jag1-induced M? polarization and the therapeutic potential of strategies of specifically targeting Jag1 in resolving inflammatory lung injury. Upon completion of these studies, we will identify not only the fundamental role of lung EC Jag1 in mediating M? polarization via interaction with Notch signaling and its significance in resolving inflammatory lung injury but also novel therapeutic approaches and targets for the treatment of ALI/ARDS.

Public Health Relevance

The focus of Project 3 in the context of the Program Project is to delineate key mechanisms involving the resolution of inflammatory lung injury and enhancing lung tolerance to subsequent infection via the interaction of the regulatory proteins Jag1 in lung endothelial cells and Notch in macrophages. We will thereby develop novel therapeutic strategies for treatment of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077806-13
Application #
9241428
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Aggarwal, Neil Raj
Project Start
2005-08-01
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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