Trauma induced endothelial cell Ca2+ signaling

这份提案描述了一项为期5年的计划(2年指导，3年独立) 在心血管疾病和创伤病理生理学研究方面的学术发展 重视离子通道功能和钙信号转导途径。科利尔博士(申请人)有以下背景 离子通道结构与功能、生物化学和分子生物学。他参加了他的博士培训 爱荷华大学分子生理学和生物物理系在Dr。 彼得·斯奈德。他以博士后的身份来到佛蒙特州大学学习新的钙离子技能 影像、血管生物学和创伤损伤的动物模型，以帮助他向 独立调查员。 佛蒙特州大学(UVM)因其在药理学方面的实力而得到国际公认， 在钙离子信号、血管生物学和创伤方面的独特专业知识。马克·纳尔逊博士将指导科利尔博士的 科学发展和向自主过渡。纳尔逊博士是钙离子领域公认的领导者 信号和血管生物学。纳尔逊博士培养了许多博士后研究员和研究生， 他们中的许多人现在是老牌的独立调查人员。Kalev Freeman，医学博士，博士将共同指导Dr。 科利尔。弗里曼博士在创伤病理生理学方面提供了独特的临床观点和专业知识。这 研究环境最大限度地提高了科利尔博士建立科学利基的潜力，从这个利基中 学术生涯是可以构建的。该项目将促进持续的技术、智力和 专业培训将帮助科利尔博士发展一套独特的技能，使他能够建立 在他选择的学术研究机构中的独立实验室。 创伤性损伤是一个主要的公共卫生问题。创伤占3700万人次的医院就诊次数， 据估计，每年给美国造成的损失超过7000亿美元。创伤性脑损伤占1.7% 数以百万计的医院就诊，往往让幸存者患有心血管并发症，如 高血压、低血压、凝血障碍和中风。这些全身性并发症的机制是 未知。已经证明，创伤会将有毒的细胞内成分释放到细胞内。 然而，关于这些有毒因素是如何在分子水平上影响组织的，人们对全身循环知之甚少。 该项目将阐明下列系统性动脉内皮细胞功能持续改变的基础 创伤相关循环因子诱导内皮细胞钙信号转导的机制，以及 颅脑损伤后维持脑动脉功能的基础。

This proposal describes a 5-year program (2 years mentored, 3 years independent) for the development of an academic career in cardiovascular disease and trauma pathophysiology research with an emphasis on ion channel function and Ca2+ signaling pathways. Dr. Collier (the applicant) has a background in ion channel structure and function, biochemistry, and molecular biology. He competed his doctoral training in the Department of Molecular Physiology & Biophysics at the University of Iowa under the mentorship of Dr. Peter Snyder. He came to the University of Vermont as Postdoctoral Associate to develop new skills in Ca2+ imaging, vascular biology, and animal models of traumatic injury to aid his transition toward becoming an independent investigator. The University of Vermont (UVM) is internationally recognized for its strength in pharmacology, with unique expertise in Ca2+ signaling, vascular biology, and trauma. Mark Nelson, Ph.D. will mentor Dr. Collier's scientific development and transition to independence. Dr. Nelson is a recognized leader in the field of Ca2+ signaling and vascular biology. Dr. Nelson has trained numerous postdoctoral fellows and graduate students, many of whom are now established independent investigators. Kalev Freeman, M.D., Ph.D. will co-mentor Dr. Collier. Dr. Freeman provides unique clinical perspective and expertise in trauma pathophysiology. This research environment maximizes the potential for Dr. Collier to establish a scientific niche from which an academic career can be constructed. This project will facilitate continued technical, intellectual, and professional training which will help Dr. Collier develop a unique skill set that will allow him to establish an independent laboratory at an academic research institution of his choosing. Traumatic injury is a major public health problem. Trauma accounts for 37 million hospital visits and is estimated to cost the U.S. more than $700 billion each year. Traumatic brain injury (TBI) accounts for 1.7 million hospital visits and often leaves survivors suffering from cardiovascular complications such as hypertension, hypotension, coagulopathy, and stroke. The mechanism of these systemic complications is unknown. It has been demonstrated that traumatic injury releases toxic intracellular components into the systemic circulation, however, little is known about how these toxic factors affect tissue at the molecular level. This project will elucidate the basis of persistent altered endothelial cell function in systemic arteries following TBI, the mechanism by which trauma associated circulating factors induced endothelial cell Ca2+ signaling, and the basis of preservation of cerebral artery function following TBI.