Discovering and Developing Recombinant Molecular Scavenging Agents for the Treatment of Carbon Monoxide Induced Cardiovascular Dysfunction

项目摘要/摘要 杰森·罗斯博士正在重新提交这份申请，申请一项名为 发现和开发用于处理一氧化碳的重组分子清除剂 (Co)引起心血管功能障碍“。罗斯医生是一名肺部和重症监护内科医生，现在 匹兹堡大学医学助理教授寻求分子方面的额外培训 工程学、线粒体生物学、疾病动物模型和药物发现，以进一步发展为 独立研究调查员。他的长期目标是领导大型学术药物设计、发现和 发展计划。对于这个提议，他的短期培训目标是：(1)熟练掌握 在疾病动物模型中评估心血管病理生理学，并发展成为 研究线粒体功能障碍在人类疾病中的作用的主要研究员；(2)在以下方面获得专业知识 分子工程、靶向药物设计和药物发现分析开发；以及(3)开发 管理技能，以成为新疗法早期开发的专家。建立在他的基础上 刚刚从泰珀商学院MBA项目毕业的他将在培训中补充说教 分子药理学、药物发现和心血管生理学课程。他召集了专家 在药物发现、心血管动力学和线粒体生物学方面形成一个有凝聚力的导师团队，并 科学顾问委员会。拟议的工作将在肺、过敏科、 匹兹堡大学的重症监护，该校在培训内科科学家和 为他的研究和学术独立之路提供了一流的基础设施。 CO暴露是世界上中毒的主要原因，目前尚无CO的解毒剂。当前干预措施 疗效有限：需要新的治疗方法。这项提案的中心目标是进一步确定 并开发一种治疗一氧化碳中毒的解毒剂。目标1将侧重于建立CO- 诱发心血管毒性：研究一氧化碳引起的线粒体抑制和血流动力学 在严重一氧化碳中毒的小鼠模型中。目的2将测试重组脑红蛋白的有效性和安全性 逆转一氧化碳中毒引起的分子和心脏功能障碍。目标3将寻求识别新的亚铁血红素 含有CO清除剂的分子，使用一种新的制造工艺和发现分析。虽然 这个提议是雄心勃勃的，罗斯博士现在已经在他紧张的临床和研究期间完成了他的MBA学位 训练展示了他在学术环境中同时处理多项任务的能力。(1)正规培训相结合 心血管生理学、创新和分子药理学；(2)新的研究经验 包括疾病建模、药物开发和发现要素；(3)经验丰富、多样化的指导 团队和咨询委员会；以及(4)匹兹堡大学强大的制度环境将 为罗斯博士的职业生涯做好准备，成为一名独立的研究调查员和学术药物发现领导者。

Project Summary/Abstract Dr. Jason Rose is resubmitting this application for a Mentored Research Career Development Award entitled “Discovering and Developing Recombinant Molecular Scavenging Agents for the Treatment of Carbon Monoxide (CO) Induced Cardiovascular Dysfunction”. Dr. Rose is a pulmonary and critical care physician, and now, Assistant Professor of Medicine at the University of Pittsburgh seeking additional training in molecular engineering, mitochondrial biology, animal models of disease, and drug discovery to further develop into an independent research investigator. His long-term goal is to lead large academic drug design, discovery and development programs. His short-term training goals, for this proposal, are to: (1) acquire proficiency in the assessment of cardiovascular pathophysiology in animal models of disease and develop the skillset to become a primary investigator in studying the role of mitochondrial dysfunction in human disease; (2) gain expertise in molecular engineering, targeted drug design and drug discovery assay development; and (3) develop the management skills to become an expert in the early-stage development of new therapeutics. Building on his recent graduation from the Tepper School of Business MBA program, he will supplement his training with didactic courses in molecular pharmacology, drug discovery and cardiovascular physiology. He has assembled experts in drug discovery, cardiovascular dynamics, and mitochondrial biology to form a cohesive mentor team and scientific advisory committee. The proposed work will be conducted within the Division of Pulmonary, Allergy, and Critical Care at the University of Pittsburgh, which has a strong history of training physician scientists and provides a superb infrastructure for his research and his path to academic independence. CO exposure is the leading cause of poisoning in the world and there is no antidote to CO. Current interventions have limited effectiveness: new therapies are needed. The central objective of this proposal is to further identify and develop an antidotal therapy for CO poisoning. Aim 1 will focus on establishing the mechanisms of CO- induced cardiovascular toxicity: investigating CO-induced mitochondrial inhibition and measuring hemodynamics in a severe CO poisoning mouse model. Aim 2 will test the efficacy and safety of recombinant neuroglobin to reverse the molecular and cardiac dysfunction caused by CO toxicity. Aim 3 will seek to identify novel heme containing molecules as CO scavengers, using a new manufacturing process and discovery assays. Although this proposal is ambitious, Dr. Rose has now completed his MBA degree during his intense clinical and research training demonstrating his ability to multitask in the academic environment. The combination of (1) formal training in cardiovascular physiology, innovation and molecular pharmacology; (2) novel research experience that includes disease modeling, drug development and discovery elements; (3) an experienced, diverse mentorship team and advisory committee; and (4) the strong institutional environment at the University of Pittsburgh will equip Dr. Rose for a career as an independent research investigator and academic drug discovery leader.