Non Muscle Myosin II Contractility Putatively Regulates Scar Contracture

描述（由申请人提供）：纤维收缩性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。对于预防纤维收缩性疾病的新型小分子药物存在未满足的需求，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收缩性是导致纤维收缩性疾病进展的主要原因。假设非肌肉肌球蛋白II是成纤维细胞和肌成纤维细胞中促进收缩性的最终共同效应蛋白。据推测，非肌肉肌球蛋白II的阻断将阻止纤维收缩性疾病的进展。非肌肉肌球蛋白II亚型的表达将在人类ibrocrettile病变组织，并在收缩动物伤口。将在动物模型中研究非肌肉肌球蛋白II抑制对纤维收缩性疾病进展的影响。功能获得、功能丧失和功能恢复方法将用于证明该蛋白在体外收缩性测定中的功能意义。该候选人是一个委员会认证的普通外科医生，谁已经完成了三年的基础伤口愈合研究，并预计将完成三年的整形外科培训在杜克大学医学中心在2008年7月。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，并在病理学方面获得任命。他的短期职业发展目标是建立外科医生科学家的职业生涯，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对纤维收缩性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型药物，将这项基础科学研究转化为临床应用。候选人的主要导师是Salvatore V. Pizzo，MD，PhD，病理学主席，DUMC医学科学家培训计划的前任主任，他的两位同事是L。DUMC整形外科主任Scott Levin医学博士和杜克大学生物系主任丹尼尔P Kiehart博士研究果蝇非肌肉肌球蛋白II功能和伤口愈合。候选人预计最初在Pizzo博士的实验室工作3年，然后逐步走向独立，在Keenan整形外科实验室工作2年，担任外科医生科学家，并最终在5年结束时准备R 01。

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.