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

描述（由申请人提供）：项目概述：候选人：Clines博士于1991年在德克萨斯大学西南医学中心获得医学博士和博士学位。在他的研究生学习中，他开发了定位克隆技术来快速识别导致骨骼发育不良的人类基因。他于2001年在杜克大学医学中心完成了内科住院医师培训。随后，她获得了弗吉尼亚大学Theresa Guise博士实验室的内分泌学奖学金，研究转移性骨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，目标是成为一名独立的学术医师兼科学家。克莱因博士将学习新的癌症生物学实验室技术，并参加课程和会议。

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.