This application proposes funding for the development of an independent research program by the principal investigator. The applicant has received excellent clinical and research training, electing to spend six years in the National Institutes of Health intramural program to gain experience in laboratory and clinical research. The applicant is now relocating to The University of Michigan, Department of Medicine. The medical center has an outstanding record for contributing protected time, resources, and the talents and experience of the faculty toward the development of physician scientists. Additionally, the proposed sponsors have demonstrated expertise in the proposed areas of research and in the training of investigators. The research proposal will examine the interrelationships between the nervous and immune systems which are intimately intertwined through overlapping expression of regulatory mediators and receptors. Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, is also secreted in peripheral inflammatory sites where it can act to modulate inflammation. Local CRH expression parallels the severity of inflammation in animal models of arthritis and in patients with rheumatoid arthritis. CRH polypeptide isolated from rheumatoid synovial tissues and fluids is indistinguishable from hypothalamic CRH by HPLC analysis and is present in concentrations similar to that of the hypophyseal venous circulation. This proposal will build on these observations by defining mechanisms through which local CRH participates in the inflammatory process.
The specific aims of the proposal are: (1) to characterize the CRH receptor on cultured rheumatoid synoviocytes and to determine if CRH transduces signal through activation of adenylyl cyclase; (2) to explore mechanisms by which CRH exerts modulatory effects on the inflammatory process by analysis of inflammatory mediator production by rheumatoid synoviocytes after treatment with CRH; (3) to examine regulation of peripheral nervous system CRH expression during inflammation; (4) to study regulation of CRH production and release in mononuclear inflammatory cells; and (5) to evaluate the importance of CRH in inflammatory arthritis using the antigen-induced arthritis model in Lewis rats. This application for the Clinical Investigator Award is grounded on the commitment of the principal investigator to a career in academic rheumatology, the expertise of the proposed sponsors, and the overall strength of the institution. These studies will provide further support for CRH as a novel modulator of the inflammatory process and lay the groundwork for investigation of this neuropeptide as a target for intervention in the treatment of human autoimmune and inflammatory diseases.
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