Functional Characterization of Prostaglandin D2 in Chronic Spontaneous Urticaria

点击翻译按钮获取中文摘要

ABSTRACT This K23 Mentored Career Development Award will provide Eric T. Oliver, MD, with the skills and training necessary for a career as an independent investigator equipped to advance our understanding of allergic skin disease. Urticaria affects 25% of individuals during their lifetime and is the cardinal symptom of many allergic reactions including anaphylaxis. Despite this, little is known of the pathogenesis of chronic forms of urticaria that affect ~1% of the population. Nearly all of these individuals lack an identifiable cause for their symptoms and are thus classified as having chronic spontaneous urticaria (CSU). Treatment is aimed at reducing pruritus and lesion severity, yet a substantial portion of CSU patients are refractory to current FDA-approved therapies. The lack of a clear pathogenesis has prevented the development of safe and effective therapies for refractory CSU. Dr. Oliver proposes that prostaglandin D2 (PGD2) is a key mediator in CSU skin lesions and promotes the urticarial response by activating leukocytes and keratinocytes. Biopsies of CSU skin lesions reveal evidence of mast cell degranulation, keratinocyte activation, and a leukocyte-predominant inflammatory infiltrate. Upon activation, mast cells synthesize and release copious quantities of PGD2, which serves as the primary ligand for the CRTh2 receptor. Through CRTh2, PGD2 and its metabolites mediate a number of activating effects on leukocytes including chemotaxis and Th2 cytokine production. Dr. Oliver discovered that blood leukocytes from CSU patients display decreases in surface CRTh2 expression and function, consistent with in vivo PGD2 exposure. Additionally, he found that treatment with an oral CRTh2 antagonist increases CRTh2 expression, increases circulating eosinophils, and decreases patient-reported itch in CSU patients. Building on Dr. Oliver's previous work, this proposal will establish the novel functional effects of PGD2 on leukocyte activation, define the production of PGD2 and its metabolites in CSU skin lesions, and determine the activating effects of PGD2 on human skin explants. This career development award will provide Dr. Oliver with the support necessary to establish himself as an independent clinician scientist focused on the pathogenesis and treatment of CSU. He has assembled a mentoring team led by Dr. Sarbjit Saini, an internationally- recognized expert in chronic urticaria. The other members of his mentoring team (Drs. Franklin Adkinson, Luis Garza, and Donald MacGlashan) all have track records of mentoring young investigators and conducting NIH- funded studies. His career development plan will bolster his knowledge of basic immunology and clinical investigation, while he also develops proficiency in dermatologic research procedures and techniques. This project will be conducted at the Johns Hopkins Asthma and Allergy Center, a national referral center for CSU. He will also utilize his collaborations with the NIH to enrich his research and training experience. Successful completion of the proposed work will assure Dr. Oliver's successful transition to an independent investigator and advance our understanding of the effects of PGD2 in human disease.