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

肿瘤源性内皮素-1在骨微环境中的分子作用

基本信息

批准号：
7250923
负责人：
GREGORY A CLINES
金额：
$ 13.63万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7250923
关键词：
Academic Medical Centers Academic Training Automobile Driving Binding Bone Development Bone Diseases Breast Breast Cancer Cell Cadherins Cancer Biology Cancer cell line Clinical Critical Pathways Development Doctor of Medicine Doctor of Philosophy Endocrinology Endothelin A Receptor Endothelin-1 Environment Faculty Fellowship Genes Genetic Transcription Goals Head Health system Homologous Gene Human Internal Medicine Invaded Laboratories Learning Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Medical center Mentors Messenger RNA Metastatic Neoplasm to the Bone Modeling Molecular Molecular Biology Techniques Mus Neoplasm Metastasis Osteoblasts Osteogenesis Pain Phosphotransferases Physicians Physiological Pre-Clinical Model Prostate Protein Overexpression Proteins Research Research Training Residencies Response Elements Role Scientist Signal Transduction Site Snails Students Techniques Testing Texas Therapeutic Intervention Training Programs Tumor-Derived Universities University of Virginia Cancer Center Virginia bone bone cell cancer cell design disability men mouse model neoplastic cell positional cloning pre-clinical prevent promoter research study response skeletal dysplasia symposium tumor

项目摘要

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.

描述（由申请人提供）：项目摘要：候选人： Clines 博士获得医学博士和博士学位。 1991 年，他作为德克萨斯大学西南医学中心医学科学家培训项目的学生获得了博士学位。在研究生学习中，他开发了定位克隆技术，可以快速识别导致骨骼发育不良的人类基因。 Clines 博士于 2001 年在杜克大学医学中心完成了内科住院医师实习。随后，在弗吉尼亚大学 Theresa Guise 博士的实验室中获得了内分泌学奖学金，研究转移性骨病的分子机制和内皮素的作用。 1（ET-1）。他于 2005 年 7 月加入弗吉尼亚大学卫生系统分校，目标是成为一名独立的学术医师兼科学家。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：Clines 博士的共同导师 Theresa Guise 博士是骨骼转移分子机制研究领域的世界领先者，将指导他使用小鼠骨转移模型。他的另一位合作导师 John Chirgwin 博士将就分子生物学技术的正确应用向他提供建议。博士。 Henry Kronenberg 和 Barry Gumbiner 将就 Wnt 信号在骨发育和转移中的作用提供出色的指导。 Richard Santen 博士将协助 Clines 博士设计和解释细胞信号传导实验。由 Michael Weber 博士领导的弗吉尼亚大学癌症中心和内分泌科为基础、临床前和临床层面的癌症和骨骼方面的学术培训和研究提供广泛的支持。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 博士确定了成骨细胞中受 ET-1 调节的主要因子：dickkopf 同源物 1 (Dkk1) 和 snail 同源物 1 (Snai1)。他推测这两个因素通过激活经典 Wnt 信号传导并驱动成骨细胞骨转移的形成来刺激成骨细胞。提出三个目标：1）确定Dkk1在成骨细胞骨转移中的生理意义； 2)确定Snai1在调节成骨细胞经典Wnt信号传导中的作用； 3)确定ET-1如何调节Dkk1和Snai1的表达。相关性：骨转移会导致严重且持久的疼痛和残疾，这是恶性循环的结果——入侵的癌细胞会产生激活骨细胞的因子，骨细胞会产生额外的因子，进而刺激癌细胞。克莱斯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措施。