MDR-1 EXPRESSION IN INFLAMMATORY BOWEL DISEASE

描述（改编自应用程序） 一个研究项目将由申请人，理查德J法雷尔医学博士， 在贝斯以色列女执事医疗中心的胃肠病学部门 （BIDMC）。法雷尔博士有大量的基础和临床研究经验 在都柏林和波士顿的胃肠病学研究期间， 表现出令人印象深刻的生产力和承诺的学术生涯中的病人 导向研究。Ciaran P. Kelly博士，内科副医师 胃肠病学，BIDMC和J托马斯拉蒙博士，胃肠病学主任， BIDMC将担任导师。尽管我们已经取得了令人印象深刻的进步， 在炎症性肠病（IBD）的诊断和管理中， 20%的溃疡性结肠炎（UC）患者和超过三分之一的患者 克罗恩病（CD）患者患有常规药物治疗难治性疾病 治疗，特别是糖皮质激素。这往往导致多个 住院和手术的需求。多药耐药 基因（MDR-1）编码基于细胞膜的药物外排泵（Pp-170）， 主动转运MDR底物，包括糖皮质激素和其他 用于管理IBD的免疫抑制剂，从靶细胞中排出，从而降低 其细胞内浓度降低到亚治疗水平。长期目标 本项目的目的是确定MDR功能的抑制是否影响 IBD患者对糖皮质激素和其他免疫抑制剂反应 疗法本申请的基本假设是， 糖皮质激素难治性IBD与MDR的过度表达直接相关。的 该项目的具体目标是：1）确定人类的水平是否 外周血淋巴细胞（PBL）MDR表达与疾病无关 活性，是IBD患者对以下药物反应的重要决定因素： 2）测定MDR表达水平 显著影响细胞内PBL糖皮质激素水平和功能 IBD患者中的组成性PBL MDR水平;以及3）确定组成性PBL MDR水平是否与IBD患者中的组成性PBL MDR水平相关。 表达是由基因决定的。除了研究部分外， 申请人将在哈佛公共学院攻读公共卫生硕士学位 健康这将包括在1）研究伦理，2） 临床流行病学，3）生物统计学，4）临床试验，5）统计学 医学研究原则。大量的研究、教育和 哈佛医学院哈佛消化疾病中心的临床资源 公共卫生和BIDMC胃肠病学部门将致力于 申请人应确保成功实现本奖项的目标。

DESCRIPTION (adapted from the application) A research program will be undertaken by the applicant, Richard J Farrell MD, in the Division of Gastroenterology at the Beth Israel Deaconess Medical Center (BIDMC). Dr. Farrell has had substantial basic and clinical research exposure during his Gastroenterology fellowships in Dublin and Boston, during which he showed impressive productivity and commitment to an academic career in patient orientated research. Dr Ciaran P. Kelly, Associate Physician in the Division of Gastroenterology, BIDMC, and Dr J Thomas LaMont, Chief of Gastroenterology at BIDMC will serve as mentors. Despite the impressive strides that have been made in the diagnosis and management of inflammatory bowel disease (IBD), as many as 20% of patients with ulcerative colitis (UC) and over one-third of patients with Crohn's disease (CD) have disease which is refractory to routine medical therapy, particularly glucocorticoids. This frequently results in multiple hospital admissions as well as the need for surgery. The Multidrug Resistance gene (MDR-1) encodes a cell membrane based drug efflux pump (Pp-170) which actively transports MDR substrates, including glucocorticoids and other immunosuppressants used to manage IBD, out of target cells thereby lowering their intracellular concentration to subtherapeutic levels. The long term goal of this project is to determine whether inhibition of MDR function influences the response of IBD patients to glucocorticoids and other immunosuppressive therapy. The underlying hypothesis for this application is that glucocorticoid-refractory IBD is directly related to overexpression of MDR. The specific aims of this project are; 1) To determine whether the level of human peripheral blood lymphocyte (PBL) MDR expression is independent of disease activity and is an important determinant of the response of IBD patients to glucocorticoids; 2) To determine whether the level of MDR expression significantly influences intracellular PBL glucocorticoid levels and function in IBD patients; and 3) To determine whether the level of constitutive PBL MDR expression is genetically determined. In addition to the research component the applicant will undertake a Masters in Public Health at Harvard School of Public Health. This will include formal research training in 1) Research ethics, 2) Clinical epidemiology, 3) Biostatistics 4) Clinical trials, and 5) Statistical Principles in Medical Research. The very substantial research, educational, and clinical resources of the Harvard Digestive Diseases Center, Harvard School of Public Health and the BIDMC Gastroenterology Division will be committed to the applicant to ensure successful attainment of the goals of this award.