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

描述（由申请人提供）：项目摘要：候选人：Dr. Clines获得了医学博士学位。和博士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学位。在他的研究生学习中，他开发了定位克隆技术，以快速识别负责骨骼发育不良的人类基因。克莱恩博士于2001年在杜克大学医学中心完成了内科住院医师的工作。随后在弗吉尼亚大学Theresa Guise博士的实验室获得了内分泌学奖学金，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，目标是成为一名独立的学术医生科学家。Clines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。 工作环境：Clines博士的共同导师Theresa Guise博士是骨转移分子机制研究的世界领导者，并将指导他使用小鼠骨转移模型。他的另一位共同导师John Chirgwin博士将就分子生物学技术的正确应用向他提供建议。亨利Kronenberg和巴里Gumbiner博士将给予突出的指导作用的Wnt信号在骨发育和转移。Richard Santen博士将协助Clines博士设计和解释细胞信号实验。由Michael Weber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，临床前和临床水平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引起成骨细胞骨转移。Clines博士已经确定了在成骨细胞中由ET-1调节的主要因子：dickkopf同源物1（Dkk 1）和snail同源物1（Snai 1）。他的理论是，这两种因子通过激活经典Wnt信号并驱动成骨细胞骨转移的形成来刺激成骨细胞。提出了三个目标：1）确定Dkk 1在成骨细胞骨转移中的生理学意义; 2）确定Snai 1在调节成骨细胞经典Wnt信号传导中的作用;以及3）确定ET-1如何调节Dkk 1和Snai 1的表达。 相关性：恶性循环导致骨转移引起严重和持久的疼痛和残疾-侵入的癌细胞产生激活骨细胞的因子，骨细胞产生额外的因子，反过来刺激癌细胞。Clines博士的研究将调查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。

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.