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: 10213117
• 负责人: Jason J Rose
• 金额: $ 16.19万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213117
• 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; 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; 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; 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.

项目摘要/摘要 杰森·罗斯（Jason Rose）博士正在将此申请重新提交为指导的研究职业发展奖，标题为 “发现并开发重组分子清除剂以治疗一氧化碳 （CO）诱导心血管功能障碍。罗斯博士是一位肺和重症医师，现在 匹兹堡大学医学助理教授，寻求分子的额外培训 工程，线粒体生物学，疾病动物模型和药物发现，以进一步发展为 独立研究研究者。他的长期目标是领导大型的学术药物设计，发现和 开发计划。他的短期培训目标（对于此提案）是：（1）熟练 评估疾病动物模型中心血管病理生理学的评估，并发展技巧 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）获得专业知识 分子工程，有针对性的药物设计和药物发现评估开发； （3）发展 成为新治疗学早期发展的专家的管理技能。建立在他的基础上 Tepper商业MBA课程的最新毕业，他将补充他的教学培训 分子药理学，药物发现和心血管生理学课程。他已经组装了专家 在药物发现，心血管动力学和线粒体生物学中，组成一个有凝聚力的心理团队和 科学咨询委员会。拟议的工作将在肺部，过敏， 匹兹堡大学的重症监护 为他的研究和他的学术独立道路提供了一流的基础设施。 CO暴露是世界上毒的主要原因，并且没有解毒剂。 有效性有限：需要新的疗法。该提议的核心目的是进一步确定 并开发用于CO中毒的解毒疗法。 AIM 1将着重于建立共同的机制 诱导心血管毒性：研究共同诱导的线粒体抑制和测量血液动力学 在严重的CO中毒小鼠模型中。 AIM 2将测试重组神经球蛋白的效率和安全性 反转由CO毒性引起的分子和心脏功能障碍。 AIM 3将寻求识别新颖的血红素 使用新的制造过程和发现分析，将分子作为Co清除剂。虽然 罗斯博士在激烈的临床和研究期间已经完成了他的MBA学位 培训表明他在学术环境中可以做出多任务的能力。 （1）正规培训的组合 在心血管生理学，创新和分子药理学中； （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，多样性心态 团队和咨询委员会； （4）匹兹堡大学的强大机构环境将 Rose博士的职业生涯是独立研究人员和学术药物发现领导者。