The long-term objective of the UCSD Acute Lung Injury (ALI) SCOR continues to be generation of insights that will lead to reduction in the morbidity and mortality associated with ALI, with attention focused specifically on investigations on lung injury mechanisms that might lead to design of rational therapies.
The specific aims of this application are to continue research activities in six distinct area that address the primary SCOR objective and to maintain and expand the interactive, synergistic intra-SCOR relationships that currently exist. Five projects continue and will expand their current SCOR programs, while a new project complements existing efforts. Studies will continue using a unique clinical model of ALI (patients undergoing pulmonary thrombo-endarterectomy) that is temporally and clinically predictable, and thus provides a singular opportunity to study targeted interventions. Fundamental observations of surfactant apoprotein B structure/function relationships underlie design of a synthetic surfactant, and studies to optimize that surfactant composition, and studies to optimize that surfactant composition and delivery and to understand anti-inflammatory potential will be performed; in addition, a variety of approaches aimed at inhibition of IL-8 activity will be evaluated. Mechanisms by which surfactant modulates the phagocyte respiratory burst oxidase will be explored in detail, with the goal of developing strategies to prevent or ameliorate, ALI; a novel strategy to reach this goal by expanding surfactant phospholipid pools through expression of a phosphocholine cytidylyltransferase transgene will also be explored. Having discovered that selectin-carbohydrate interactions involve heparan sulfate, investigators will now study interactions involve heparan sulfate, investigators will now study lung L- and P-selectin expression in acute lung injury and the potential of heparin and related molecules to modify selectin interaction with native ligands. Investigators will identify and assess function of specific receptors that affect interactions between lung cells and bacterial lipopolysaccharide- protein complexes and, in a new project, the role of parathyroid hormone- related protein (PTHrP) in modifying type II cell function, growth, and apoptosis will be studied. Clinical, Tissue and Cell Laboratory, and Administrative Cores support SCOR activities; the last takes particular care to maintain and expand intra-SCOR collaborations.
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