Although significant strides have been made toward better understanding the mechanisms of immunoregulation and genetic susceptibility of chronic inflammatory disorders, including immune-mediated arthritis, diabetes, inflammatory bowel diseases, systemic lupus erythematosus (SLE), glomerulonephritis, vasculitis, atherosclerosis and asthma, a major impediment to their diagnosis and clinical management is the inability to easily determine and quantify the activity and extent of disease involving in accessible internal organs. Moreover, current techniques cannot identify subclinical inflammation that predicts rapid recurrence of symptoms after inducing remission or the on set of disease in high risk individuals. Histologic diagnosis and assessment of disease activity in the intestine, lung, liver, kidney, joint, blood vessels, thyroid and brain, require invasive endoscopic, percutaneous or even open surgical biopsy, which entail considerable discomfort and risk. Our goal is to develop noninvasive methods to determine the location and intensity of inflammation in inaccessible organs of patients with several inflammatory diseases by applying basic knowledge of the mechanisms of vascular endothelial/ effector inflammatory cell interactions, activation of innate and acquired immune cells, vascular permeability and neovascularization to novel imaging techniques. Our studies will focus on Crohn's disease, ulcerative colitis, SLE, anti-neutrophil cytoplasmic antibody (ANCA)-mediated vasculitis and atherosclerosis because interdisciplinary research programs that encompass basic mechanistic, animal model and clinical investigations in these disorders exist in our institution, each are multiorgan conditions, and these diseases are prototypes of T lymphocyte, antibody/complement, neutrophil and macrophage-mediated disorders, respectively. Results from these focused studies will therefore be applicable to all of the previously mentioned inflammatory conditions. The following Specific Aims will approach this goal: 1. Develop an administrative structure that will plan and coordinate activities and promote effective interactions and communication among a multidisciplinary group of investigators. 2. Organize topic-driven workshops promoting interactions between local investigators and external experts to define the optimal molecular targets, detection techniques and clinical applications for determining the extent and activity of inflammation in a variety of organs and disease processes. 3. Support pilot studies to define molecular targets (1st year), optimize imaging and molecular/biochemical/immunologic techniques (1st and 2nd years), validate these targets and techniques in animal models of inflammatory conditions in diverse organs (2nd year), and perform pilot studies in targeted human inflammatory diseases applying the results of the basic and animal model studies (3rd year). This translational, clinically applied research will involve a multidisciplinary, interactive group of >60 investigators derived from 9 departments and 7 centers in 5 schools of 3 universities and the Environmental Protection Agency. This well organized planning process will result in clinically relevant outcomes that can be quickly optimized for application to a number of important inflammatory diseases in multiple organs. This project will create a new program involving investigators who have not previously worked together, while building on institutional strengths and programmatic initiatives.
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