Functional Characterization of Prostaglandin D2 in Chronic Spontaneous Urticaria

摘要 这个K23指导职业发展奖将提供埃里克T。奥利弗，医学博士，与技能和培训 作为一名独立的研究人员，有必要提高我们对过敏性皮肤的理解 疾病荨麻疹影响25%的个人在其一生中，是主要的症状，许多过敏 包括过敏反应在内的反应。尽管如此，很少有人知道慢性荨麻疹的发病机制 影响了约1%的人口。几乎所有这些人都缺乏一个可识别的原因，他们的症状 因此被归类为患有慢性自发性荨麻疹（CSU）。治疗的目的是减少瘙痒 和病变严重程度，但相当一部分CSU患者对目前FDA批准的治疗是难治的。 缺乏明确的发病机制阻碍了难治性肿瘤安全有效治疗的发展。 鉴证组奥利弗博士提出，前列腺素D2（PGD 2）是CSU皮肤病变的关键介质， 通过激活白细胞和角质形成细胞引起荨麻疹反应。CSU皮肤病变的活检显示 肥大细胞脱颗粒、角质形成细胞活化和白细胞为主的炎性 潜入在激活时，肥大细胞合成并释放大量的PGD 2，其充当细胞的免疫调节剂。 CRTh 2受体的主要配体。通过CRTh 2，PGD 2及其代谢产物介导了许多 对白细胞的活化作用，包括趋化性和Th 2细胞因子产生。奥利弗博士发现 来自CSU患者的血液白细胞显示表面CRTh 2表达和功能降低，与 体内PGD 2暴露。此外，他发现口服CRTh 2拮抗剂治疗增加了 CSU患者CRTh 2表达增加，循环嗜酸性粒细胞增加，并减少患者报告的瘙痒。 在奥利弗博士先前工作的基础上，这项提议将建立PGD 2对人乳腺癌的新功能作用。 白细胞活化，确定CSU皮肤病变中PGD 2及其代谢产物的产生，并确定 PGD 2对人皮肤外植体的活化作用。这个职业发展奖将为奥利弗博士提供 必要的支持，以建立自己作为一个独立的临床科学家集中在发病机制 CSU的治疗。他组建了一个由Sarbjit Saini博士领导的指导团队，Sarbjit Saini博士是一位国际- 慢性荨麻疹专家他的指导团队的其他成员（富兰克林阿德金森博士，路易斯 Garza和Donald MacGlashan）都有指导年轻研究人员和指导NIH的记录- 资助的研究。他的职业发展计划将加强他的基础免疫学和临床 他还精通皮肤病学研究程序和技术。这 该项目将在约翰霍普金斯哮喘和过敏中心进行，该中心是CSU的国家转诊中心。 他还将利用与NIH的合作来丰富他的研究和培训经验。成功 完成拟议的工作将确保奥利弗博士成功地过渡到一个独立的研究者 并促进我们对PGD 2在人类疾病中作用的理解。

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.