CLOTRIMAZOLE THERAPY FOR HUMAN DIARRHEAL DISEASES

研究：这个转化研究项目的目标是测试克霉唑（CLT）在治疗牙周炎疾病中的疗效。我们以前曾报道，CLT抑制肠液分泌在体外和体内通过阻断基底外侧膜钾离子通道在肠上皮细胞。我们最近发现，用于治疗HIV感染患者的蛋白酶抑制剂（PI）在培养的肠上皮细胞中引起C1分泌应答，该应答被CLT完全抑制。分泌性腹泻可能是PI治疗的剂量限制性副作用，有效抗分泌治疗的开发将扩大这些重要抗治疗的效用，有效抗分泌治疗的开发将扩大这些重要抗病毒剂的效用。在最近的研究中，我们发现CLT抑制中性粒细胞（PMN）穿过培养的肠上皮T84细胞单层的迁移。中性粒细胞移行和粘膜溃疡是所有炎性和感染性水肿的基础。在拟定的临床研究中，我们将测试口服CLT治疗在高输出量回肠造口患者和服用HIV-1蛋白酶抑制剂奈非那韦患者中发现的分泌性腹泻的疗效。在一项单独的研究中，我们将测试局部CLT在远端肠道炎症（结肠袋炎）患者中的疗效。候选人：Rufo博士是一位训练有素的儿科胃肠病学家，致力于在转化研究领域从事学术医学事业。他的基本发现导致了两个第一作者的出版物在临床研究杂志上，并建立了临床试验的科学依据。鲁弗博士一直是一个富有成效的研究人员，并有明确的潜力成为一个创造性的调查。我们将投入80%的努力，在这个赠款申请概述的培训计划。环境：鲁弗博士已被分配到儿童医院胃肠科的办公室，并将继续参加韦恩兰瑟博士的上皮细胞生物学小组。此外，Rufo博士将参加哈佛消化疾病中心和哈佛/麻省理工学院科学界举办的研讨会和研究会议。Patricia Hibbirth博士将担任Rufo博士的临床研究导师。一个备受尊敬的个人（在校园）小组已被安排监督这项研究培训和职业发展。为了接受生物统计学、流行病学和研究伦理学方面的正式培训，Rufo博士将在哈佛医学院完成医学科学硕士学位课程。

The Research: The goals of this translational research project are to test the efficacy of clotrimazole (CLT) in the treatment of diarrheal disease. We have previously reported that CLT inhibits intestinal fluid secretion in vitro and in vivo by blocking basolateral membrane K+ channels in enterocytes. We have recently discovered that protease inhibitors (PI's) used in the treatment HIV infected patients elicit a C1-secretory responses in cultured intestinal epithelial cells that is inhibited fully by CLT. Secretory diarrhea can be a dose limiting side effect of PI therapy, and the development of effective anti-secretory therapies would expand the utility of these important anti-therapy, and the development of effective anti-secretory therapies would expand the utility of these important anti-viral agents. In more recent studies, we have found that CLT inhibits the transmigration of neutrophils (PMN's) across cultured intestinal epithelial T84 cell monolayers. PMN transmigration and mucosal ulceration underlie all inflammatory and infectious diarrheas. In the clinical studies proposed, we will test the efficacy of oral CLT therapy in the treatment of the secretory diarrhea found in patients with high output ileostomies and in patients taking the HIV-1 protease inhibitor nelfinavir. In a separate study, we will test the efficacy of topical CLT in patients with distal intestinal inflammation (pouchitis). The Candidate: Dr. Rufo is a fully trained pediatric gastroenterologist who has committed to pursuing a career in academic medicine in the area of translational research. His basic findings have resulted in two first authored publications in The Journal of Clinical Investigation, and established the scientific rationale for clinical trials proposed. Dr. Rufo has been a productive researcher, and has the clear potential to become a creative investigator. We will devote 80% effort to the training program outlined in this grant application. The Environment: Dr. Rufo has been assigned office space within the Gastroenterology Division at Children's Hospital, and will continue to participate in Dr. Wayne Lencer's epithelial cell biology group. In addition, Dr. Rufo will participate in the seminars and research meeting available through the Harvard Digestive Disease Center and the Harvard/MIT scientific communities. Dr. Patricia Hibberd will serve as Dr. Rufo's mentor in clinical research. A panel of well respected individuals (on campus) has been arranged to oversee this research training and career development. To receive formal training in biostatistics, epidemiology, and research ethics, Dr. Rufo will complete a Masters of Medical Sciences degree program at Harvard Medical School.