Molecular actions of tumor-derived endothelin-1 in the bone microenvironment

描述(由申请人提供)：项目概要：候选人：克莱斯博士于1991年在德克萨斯大学西南医学中心作为医学科学家培训项目的学生获得医学博士和博士学位。在他的研究生研究中，他开发了定位克隆技术，以快速识别导致骨骼发育不良的人类基因。克莱斯博士于2001年在杜克大学医学中心完成了内科实习。之后是弗吉尼亚大学Theresa Guise博士实验室的内分泌学研究员，研究转移性骨疾病的分子机制和内皮素-1(ET-1)的作用。他于2005年7月加入弗吉尼亚大学卫生系统学院，目标是成为一名独立的学术内科医生兼科学家。克莱斯博士将学习癌症生物学的新实验室技术，并参加课程和会议。 环境：克莱斯博士的合作导师特蕾莎·盖斯博士是骨骼转移分子机制研究的世界领先者，并将指导他使用小鼠骨转移模型。他的另一位合作导师约翰·奇格温博士将就分子生物学技术的正确应用向他提供建议。Henry Kronenberg博士和Barry Gumbiner博士将就Wnt信号在骨骼发育和转移中的作用提供出色的指导。理查德·桑顿博士将协助克莱斯博士设计和解释细胞信号实验。由迈克尔·韦伯博士领导的弗吉尼亚大学癌症中心和内分泌科为癌症和骨骼的基础、临床前和临床层面的学术培训和研究提供了广泛的支持。 研究：分泌ET-1的癌细胞通过激活成骨细胞导致成骨细胞骨转移克莱斯博士已经确定了成骨细胞中受ET-1调控的主要因素：Dickkopf同源1(Dkk1)和蜗牛同源1(Snai1)。他的理论是，这两个因素通过激活规范的Wnt信号和驱动成骨细胞骨转移的形成来刺激成骨细胞。有三个目标被提出：1)确定Dkk1在成骨细胞骨转移中的生理意义；2)确定Snai1在成骨细胞规范的Wnt信号转导中的作用；3)确定ET-1如何调节Dkk1和Snai1的表达。 相关性：由于恶性循环的结果，骨转移导致显著和持久的疼痛和残疾--侵袭的癌细胞产生激活骨细胞的因子，后者产生额外的因子，进而刺激癌细胞。克莱斯博士的研究将研究癌症和骨细胞的分子相互作用，并开发临床前模型来测试骨转移的治疗干预措施。

DESCRIPTION (provided by applicant): Project summary: Candidate: Dr. Clines obtained his M.D. and Ph.D. degrees as a Medical Scientist Training Program student at the University of Texas Southwestern Medical Center in 1991. In his graduate studies, he developed positional cloning techniques to rapidly identify human genes responsible for skeletal dysplasias. Dr. Clines completed an internal medicine residency at Duke University Medical Center in 2001. This was followed by an endocrinology fellowship at the University of Virginia in the laboratory of Dr. Theresa Guise, studying molecular mechanisms of metastatic bone disease and the role of endothelin-1 (ET-1). He joined the faculty of the University of Virginia Health System in July, 2005 with the goal of becoming an independent academic physician-scientist. Dr. Clines will learn new laboratory techniques in cancer biology and participate in coursework and conferences. Environment: Dr. Clines' co-mentor, Dr. Theresa Guise, is a world leader in research on the molecular mechanisms of skeletal metastasis and will instruct him in the use of mouse bone metastasis models. His other co-mentor, Dr. John Chirgwin, will advise him on the proper application of molecular biology techniques. Drs. Henry Kronenberg and Barry Gumbiner will give outstanding guidance on the role of Wnt signaling in bone development and metastasis. Dr. Richard Santen will assist Dr. Clines in the design and interpretation of cellular signaling experiments. The University of Virginia Cancer Center, headed by Dr. Michael Weber, and Division of Endocrinology provide extensive support for academic training and research in cancer and bone at basic, preclinical and clinical levels. Research: Cancer cells that secrete ET-1 cause osteoblastic bone metastases by activation of osteoblasts. Dr. Clines has identified major factors regulated by ET-1 in osteoblasts: dickkopf homolog 1 (Dkk1) and snail homolog 1 (Snai1). He theorizes that these two factors stimulate osteoblasts by activating canonical Wnt signaling and driving the formation of osteoblastic bone metastases. Three aims are proposed: 1) determine the physiological significance of Dkk1 in osteoblastic bone metastasis; 2) determine the role of Snai1 in regulating osteoblast canonical Wnt signaling; and 3) determine how ET-1 regulates the expression of Dkk1 and Snai1. Relevance: Bone metastases cause significant and protracted pain and disability as the result of a vicious cycle -- invading cancer cells produce factors that activate bone cells, which produce additional factors that in turn stimulate the cancer cells. Dr. Clines' research will investigate the molecular interactions of cancer and bone cells and develop preclinical models to test therapeutic interventions of bone metastasis.