Functional Characterization of Prostaglandin D2 in Chronic Spontaneous Urticaria

摘要 这项K23指导职业发展奖将为医学博士Eric T.Oliver提供技能和培训 作为一名独立研究员的职业生涯所必需的，以促进我们对过敏性皮肤的了解 疾病。在一生中有25%的人会患上荨麻疹，它是许多过敏性疾病的主要症状。 反应包括过敏反应。尽管如此，人们对慢性形式的荨麻疹的发病机制知之甚少。 这影响了大约1%的人口。几乎所有这些人的症状都没有可识别的原因。 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，然而，很大一部分CSU患者对目前FDA批准的治疗方案无效。 由于缺乏明确的发病机制，阻碍了安全有效的治疗难治性疾病的发展。 加州州立大学。奥利弗博士提出，前列腺素D2(PGD2)是CSU皮肤损害的关键介质，并促进 通过激活白细胞和角质形成细胞而引起的麻风反应。CSU皮肤病变的活组织检查显示 肥大细胞脱颗粒、角质形成细胞活化和以白细胞为主的炎症的证据 渗透进去。肥大细胞被激活后，合成并释放大量的PGD2，作为 CRTH2受体的主要配体。通过CRTH2，PGD2及其代谢产物介导了许多 对白细胞的激活作用，包括趋化作用和Th2细胞因子的产生。奥利弗博士发现 CSU患者外周血白细胞表面CRTH2表达和功能降低，一致 在体内接触PGD2。此外，他发现口服CRTH2拮抗剂的治疗增加了 CSU患者CRTH2表达增加，循环中嗜酸性粒细胞增多，患者报告的瘙痒减少。 在奥利弗博士先前工作的基础上，这项建议将建立PGD2对 白细胞活化，定义PGD2及其代谢产物在CSU皮损中的产生，并确定 前列腺素D2对人皮肤外植体的激活作用这个职业发展奖将为奥利弗博士提供 将自己确立为专注于发病机制的独立临床科学家所需的支持 和CSU的治疗。他组建了一个由Sarbjit Saini博士领导的指导团队，他是一位国际- 公认的慢性荨麻疹专家。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)都有指导年轻调查人员和指导NIH- 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知识 在从事皮肤病研究的同时，他还精通皮肤病研究程序和技术。这 该项目将在约翰霍普金斯大学哮喘和过敏中心进行，该中心是CSU的全国转诊中心。 他还将利用与美国国立卫生研究院的合作来丰富他的研究和培训经验。成功 拟议工作的完成将确保奥利弗博士成功过渡到独立调查员 并促进我们对PGD2在人类疾病中的作用的理解。

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.