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

发现和开发用于治疗一氧化碳引起的心血管功能障碍的重组分子清除剂

• 批准号: 10442531
• 负责人: Jason J Rose
• 金额: $ 2.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442531
• 关键词: Advisory Committees; Affinity; Animal Disease Models; Antidotes; Binding; Biological Assay; Biology; Blood Pressure; Businesses; Carbon Monoxide; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Catheters; Clinical; Clinical Research; Complex; Critical Care; Development; Disease model; Drug Design; Drug Kinetics; Drug Targeting; Effectiveness; Electrodes; Electron Transport; Elements; Engineering; Environment; Erythrocytes; Exposure to; Functional disorder; Generations; Globin; Glycolysis; Goals; Heart; Heart Rate; Heme; Hemoglobin; Human; Hyperbaric Oxygen; Hypersensitivity; Implant; In Vitro; Individual; Intervention; Intravenous; K-Series Research Career Programs; Lead; Level of Evidence; Lung; Measures; Mechanical ventilation; Mediating; Medicine; Mentors; Mentorship; Methods; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial dysfunction; Myoglobin; Neurocognitive Deficit; Oxidative Phosphorylation; Oxygen; Patient Care; Patients; Peptides; Peroxidases; Persons; Pharmacology; Physicians; Physiological; Poisoning; Positioning Attribute; Process; Production; Program Development; Property; Proteins; Recombinants; Recording of previous events; Research; Research Infrastructure; Research Personnel; Research Training; Respiration; Rodent Model; Role; Safety; Schools; Scientist; Survivors; System; Systems Analysis; Techniques; Testing; Tissues; Toxic effect; Toxicology; Training; United States; Universities; Work; assay development; autooxidation; base; cardiac depression; cardiovascular effects; career; cohesion; commercialization; cytochrome c oxidase; depressive symptoms; design; drug development; drug discovery; efficacy testing; experience; experimental study; extracellular; heme a; hemodynamics; high risk; human disease; hypoperfusion; improved; in vivo; innovation; manufacturing process; mitochondrial dysfunction; molecular size; mortality; mortality risk; mouse model; multitask; mutant; myocardial injury; neuroglobin; next generation; novel; novel therapeutics; peptide B; peroxidation; professor; programs; restoration; skills; small molecule; tissue respiration

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.

项目总结/摘要 博士Jason Rose正在重新提交这份申请，申请一个名为“指导研究职业发展奖”的项目。 “发现和开发用于治疗一氧化碳的重组分子清除剂 (CO)诱发心血管功能障碍”。罗斯医生是一名肺病和重症监护医生，现在， 匹兹堡大学医学助理教授，寻求分子生物学方面的额外培训 工程，线粒体生物学，疾病的动物模型，和药物发现，以进一步发展成为一个 独立调查员。他的长期目标是领导大型学术药物设计，发现和开发。 发展方案。他的短期培训目标，对于这个建议，是：（1）获得熟练的 在疾病的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者;（2）获得以下方面的专业知识 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，成为新疗法早期开发的专家。根据他 最近从泰珀商学院MBA课程毕业，他将补充他的培训与说教 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， 科学顾问委员会。拟议的工作将在肺、过敏、 和匹兹堡大学的重症监护，该大学在培养医生科学家方面有着悠久的历史， 为他的研究和学术独立提供了极好的基础设施。 接触一氧化碳是世界上导致中毒的主要原因，目前没有一氧化碳的解毒剂。 有效性有限：需要新的治疗方法。本建议的核心目标是进一步查明 开发一种一氧化碳中毒的解毒疗法目标1将侧重于建立CO- 诱导的心血管毒性：研究CO诱导的线粒体抑制并测量血流动力学 在严重CO中毒小鼠模型中。目的2将测试重组脑红蛋白对脑缺血再灌注损伤的有效性和安全性。 逆转由CO毒性引起的分子和心脏功能障碍。目标3将寻求确定新的血红素 含有分子作为CO清除剂，使用新的制造工艺和发现分析。虽然 这个计划是雄心勃勃的，罗斯博士现在已经完成了他的MBA学位，在他紧张的临床和研究 培训展示了他在学术环境中处理多项任务的能力。（1）正规培训 在心血管生理学、创新和分子药理学方面;（2）新的研究经验， 包括疾病建模，药物开发和发现元素;（3）经验丰富，多样化的指导 团队和咨询委员会;（4）匹兹堡大学强大的制度环境将 装备罗斯博士的职业生涯作为一个独立的研究调查员和学术药物发现的领导者。