Our understanding of the mechanisms underlying the induction, maintenance and resolution of the alveolar inflammatory response in acute lung injury is evolving. Hypotheses about mechanisms of lung injury have led to a number of clinical trials testing innovative therapies based on experimental models of lung injury, yet none of these have had important biologic or clinical effects in humans. The failure of many of these clinical trials shows that there is a gap between in vitro or animal studies, and large, expensive phase II/III trials that use clinically important endpoints. We need to develop a mechanism to better establish """"""""proof of concept"""""""" in humans either at risk for, or with established hmg injury. Proof of concept studies would show that the intervention affects the biologic endpoint(s) of interest in humans and lay the foundation for larger trials of clinical efficacy. The overall objective of this proposal is to develop a clinical research unit, which we refer to as a Clinical Trials Incubator Unit (CTIU). The CTIU will be a collaborative, multidisciplinary research program with two principal aims: 1) To translate biologically plausible interventions directed at either reducing lung injury or hastening repair into therapeutic strategies of potential clinical benefit using plausible biological endpoints in focused clinical trials to establish proof of concept in humans; and 2) To use new technological advances in proteomics and genomics to identify patterns of protein and gene expression in the lungs before and after the onset of acute lung injury to better define subpopulations with acute hypoxemic respiratory failure that would benefit from innovative therapies. The fulfillment of these specific aims would put in place the infrastructure and processes to identify interventions and provide an estimate of the magnitude and direction of any biologic or clinically significant effect, while defining subpopulations with lung injury that are most likely to benefit. Taken together, this process will serve to """"""""incubate"""""""" concepts in preparation for the design and implementation of Phase II/III clinical trials organized through large clinical research networks.
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