MDR-1 EXPRESSION IN INFLAMMATORY BOWEL DISEASE

说明(改编自应用程序) 申请者理查德·J·法雷尔医学博士将进行一项研究计划。 在贝丝以色列女执事医疗中心的胃肠病科 (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消化学研究期间，在此期间，他 在病人身上表现出令人印象深刻的工作效率和对学术事业的承诺 有针对性的研究。Ciaran P.Kelly博士，副内科医生 BIDMC的胃肠病学和J·托马斯·拉蒙特博士 北汽集团将担任导师。尽管已经取得了令人印象深刻的进展 在炎症性肠病(IBD)的诊断和治疗中，多达 20%的溃疡性结肠炎(UC)患者和超过三分之一的患者 患有克罗恩病(CD)的患者有常规医学难以治愈的疾病 治疗，特别是糖皮质激素。这通常会导致多个 入院以及手术的需要。多药耐药 MDR-1基因编码一种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 用于治疗IBD的免疫抑制剂，从而降低了靶细胞 他们的细胞内浓度达到亚治疗水平。长期目标 该项目的目的是确定抑制MDR功能是否会影响 炎症性肠病患者对糖皮质激素等免疫抑制剂的反应 心理治疗。这个应用程序的基本假设是 糖皮质激素难治性IBD与MDR的过度表达直接相关。这个 本项目的具体目标是：1)确定人的水平是否 外周血淋巴细胞(PBL)MDR表达与疾病无关 活动性，是IBD患者对 糖皮质激素；2)确定MDR表达水平 显著影响细胞内PBL糖皮质激素水平和功能 在IBD患者中；以及3)确定构成PBL MDR的水平 表达是由基因决定的。除了研究部分之外， 申请人将在哈佛大学公共卫生学院攻读公共卫生硕士学位 健康。这将包括1)研究伦理方面的正式研究培训，2) 临床流行病学，3)生物统计学，4)临床试验，5)统计 医学研究原理。非常实质性的研究、教育和 哈佛大学消化疾病中心临床资源 公共卫生和BIDMC消化科将致力于 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.