Purinergic Pathways in Crohn's Disease

描述(申请人提供)：莫斯博士是炎症性肠病(IBD)的初级研究员。作为一名研究员，他除了接受过胃肠病专家的临床培训外，还接受过炎症分子生物学方面的培训。在过去的两年里，他在免疫学研究方法方面得到了西蒙·罗布森博士的指导。他的近期目标是进一步发展他的免疫学和翻译研究方面的研究培训，以调查内源性免疫抑制途径在IBD中的作用。为这些疾病的患者开发未来的诊断和治疗工具将需要能够将免疫学的进步带到床边的研究人员，反之亦然。他的中期目标是为R01在这一领域的成功应用获得合适的初步数据，并通过相关的学术活动建立他的声誉。从长远来看，莫斯博士打算获得一致的资金，以维持一个独立的实验室小组，专注于IBD新疗法和诊断方法的转化性研究。这个K23的研究职业发展计划是基于免疫学的杰出导师(西蒙·罗布森博士)、拥有强大翻译研究简历的调查人员职业发展委员会以及为促进莫斯博士的独立之路而量身定做的特定课程的组合。主办机构(BIDMC)通过提升莫斯博士为初级教员和助理教授，继续提供实验室空间，保护研究时间(工资支持)，以及对他的专门指导，展示了他们对莫斯博士的持续承诺。医学系和消化内科限制了他的临床工作量，主要目的是让他有适当的时间进行实验室经验、课程学习和学术交流。拟议中的项目不仅是一个具有深远临床重要性的话题，也是一个理想的培训工具，莫斯博士将有机会巩固他现有的技能，学习新的研究技术。艾伦·莫斯博士提出的这项K23建议的目的是研究克罗恩病患者免疫调节的一条途径被改变的机制，以及某些治疗如何改变这种影响。特别是，这项计划将研究一组酶(CD39，CD73)和受体，将组织损伤的有害产物(ATP，ADP)转化为免疫抑制分子(腺苷)。在动物模型中的研究表明，这些酶对炎症具有保护作用，但它们在人类克罗恩病中的作用尚不清楚。莫斯博士的初步数据已经观察到克罗恩病患者这些酶的比例和活性发生了变化。这项建议中的实验将量化这些嘌呤能通路在克罗恩病患者和健康对照组中的存在和活性。我们将研究炎症状态如何损害它们的活动，以及某些药物(抗肿瘤坏死因子药物)的治疗如何改变它们的活性。该项目旨在为克罗恩病患者提供对这些途径的透彻了解，以便开发新的治疗方法来增强它们的免疫抑制作用。 公共卫生相关性：炎症性肠病影响近200万美国人。这项建议将提高我们对克罗恩病患者免疫系统调节的理解。它可能为患有这种疾病的患者提供新的药物治疗靶点。

DESCRIPTION (provided by applicant): Dr. Moss is a junior investigator in Inflammatory Bowel Disease (IBD). As a fellow he trained in the molecular biology of inflammation, in addition to his clinical training as a gastroenterologist. In the last 2 years he has been mentored by Dr Simon Robson in immunology research methods. His immediate goal is to further develop his immunology and research training in translational research in order to investigate the role of endogenous immuno-suppressive pathways in IBD. The development of future diagnostic and therapeutic tools for patients with these diseases will require investigators who can bring advances in immunology to the bed-side, and vice versa. His medium- term goal is to acquire suitable preliminary data for a successful R01-application in this field, and establish his reputation through relevant scholarly activities. In the long-term Dr Moss intends to obtain consistent funding to maintain an independent laboratory group focused on translational research in novel therapeutics and diagnostic methods in IBD. The research career development plan for this K23 is based on a combination of an outstanding mentor in immunology (Dr Simon Robson), a Career Development Committee of investigators with strong translational research resumes, and specific coursework tailored to foster Dr Moss's pathway to independence. The host institution (BIDMC) have demonstrated their on-going commitment to Dr Moss through his promotion to junior faculty and Assistant Professor, the continued provision of laboratory space, protected research time (salary support), and dedicated mentorship for him. The Dept of Medicine and Division of Gastroenterology have limited his clinical workload with the primary intention of allowing him appropriate time for laboratory experience, coursework and academic networking. The proposed project is not only a topic of profound clinical importance but also an ideal training vehicle in which Dr Moss will have the opportunity to solidify his existing skills and to learn new research techniques. The purpose of this K23 proposal by Dr Alan Moss is to examine the mechanisms through which one pathway of immune regulation is altered in patients with Crohn's disease, and how certain treatments modify this effect. In particular, this proposal will study a group of enzymes (CD39, CD73) and receptors that convert harmful products of tissue damage (ATP, ADP) to immuno- suppressive molecules (adenosine). Studies in animal models have suggested that these enzymes are protective against inflammation, but their role in human Crohn's disease is unknown. Preliminary data by Dr Moss has observed an alteration in the proportion and activity of these enzymes in patients with Crohn's disease. The experiments in this proposal will quantify the presence and activity of these purinergic pathways in patients with Crohn's disease, and healthy controls. We will examine how inflammatory states may impair their action, and how treatment with certain drugs (anti- TNF agents) modifies their activity. This project aims to provide a thorough understanding of these pathways in patients with Crohn's disease, so that novel treatments may be developed to enhance their immuno-suppressive roles. PUBLIC HEALTH RELEVANCE: Inflammatory Bowel Disease affects nearly 2 million Americans. This proposal will improve our understanding of regulation of the immune system in patients with Crohn's disease. It may provide novel targets for drug treatments for patients with this condition.