Non Muscle Myosin II Contractility Putatively Regulates Scar Contracture

描述(申请人提供)：纤维收缩疾病每年影响全球近8000万人；然而，目前的治疗方式相对无效。有一种新的小分子药物预防纤维收缩疾病的需求尚未得到满足，但首先需要验证疾病形成的机制。成纤维细胞和肌成纤维细胞的收缩能力可能与纤维收缩疾病的进展有关。非肌肉肌球蛋白II被认为是成纤维细胞和肌成纤维细胞中促进收缩的最终共同效应蛋白。据推测，阻断非肌肉肌球蛋白II将阻止纤维收缩疾病的进展。非肌肉肌球蛋白II亚型的表达将在人类肌肉收缩疾病的组织和收缩的动物伤口中进行研究。在动物模型中，将研究非肌肉肌球蛋白II抑制对纤维收缩疾病进展的影响。功能获得、功能丧失和功能恢复的方法将被用来证明该蛋白在体外收缩试验中的功能意义。应聘者是一名获得董事会认证的普通外科医生，他已经完成了三年的伤口愈合基础研究，预计将于2008年7月在杜克大学医学中心完成三年的整形外科培训。2008年7月，他将在杜克大学医学中心担任整形外科助理教授，并被任命为病理学专业。他的短期职业发展目标是建立外科科学家的职业生涯，拓宽他的基础科学知识基础，提高他的实验室技能，并验证非肌肉肌球蛋白II对纤维收缩疾病的进展至关重要。候选人的长期目标是通过开发一种预防纤维收缩疾病的新药，将这一基础科学研究转化为临床应用。候选人的主要导师是DUMC病理学主席、医学博士塞尔瓦托·V·皮佐和DUMC前医学科学家培训计划主任，他的两位合作者是DUMC整形外科主任L.Scott Levin医学博士和杜克大学生物系主任Daniel P Kiehart博士，他研究果蝇的非肌肉肌球蛋白II功能和伤口愈合。这位候选人预计，最初将在Pizzo博士的实验室工作3年，然后逐步走向独立，在基南整形外科实验室作为外科科学家工作2年，最终在5年结束时准备一辆R01。

DESCRIPTION (provided by applicant): Fibrocontractile disease affects nearly 80 million people worldwide annually; yet, current treatment modalities are relatively ineffective. There is an unmet need for a novel small molecule drug to prevent fibrocontractile disease but first the mechanisms of disease formation need to be verified. Fibroblast and myofibroblast contractility is putatively responsible for fibrocontractile disease progression. Non muscle myosin II is hypothesized to be the final common effector protein in fibroblasts and myofibroblasts that promotes contractility. It is hypothesized that blockade of non muscle myosin II will prevent fibrocontractile disease progression. Non muscle myosin II isoform expression will be investigated in human ibrocontractile diseased tissue, and in contracting animal wounds. The effects of non muscle myosin II inhibition on fibrocontractile disease progression in animal models will be studied. Gain of function, loss of function and return of function approaches will be used to demonstrate the functional significance of this protein in in vitro contractility assays. The candidate is a board certified general surgeon, who has completed three years of basic wound healing research, and is expected to finish three years of Plastic Surgery training at Duke University Medical Center in July, 2008. In July 2008, he will work as an Assistant Professor in Plastic Surgery at Duke University Medical Center, with an appointment in Pathology. His short-term career development goals are to establish a career as a surgeon scientist, broaden his basic science knowledge base, improve his laboratory skills and verify that non muscle myosin II is essential for fibrocontractile disease progression. The candidate's long term goals are to translate this basic science research into clinical application by developing a novel pharmaceutical to prevent fibrocontractile disease. The candidate's primary mentor is Salvatore V. Pizzo, MD, PhD, Chairman of Pathology, and previous director of the Medical Scientist Training Program at DUMC, and his two co-meritors are L. Scott Levin, MD, Chief of Plastic Surgery at DUMC, and Daniel P Kiehart, PhD, Chairman of the Department of Biology at Duke University who investigates non muscle myosin II function and wound healing in Drosophila. The candidate foresees initially working in Dr Pizzo's laboratory for 3 years, then progressing towards independence, working for 2 years in the Keenan Plastic Surgery Laboratory as a surgeon scientist, and ultimately preparing an R01 towards the end of the 5 years.