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: 9973110
• 负责人: Jason J Rose
• 金额: $ 16.18万
• 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/9973110
• 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; Mechanics; 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; 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.

项目概要/摘要 Jason Rose 博士正在重新提交这份名为“指导研究职业发展奖”的申请 “发现和开发用于处理一氧化碳的重组分子清除剂 (CO) 诱发的心血管功能障碍”。罗斯博士是一名肺科和重症监护医生，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、线粒体生物学、疾病动物模型和药物发现，进一步发展为 他的长期目标是领导大型学术药物设计、发现和研究。 对于该提案，他的短期培训目标是：（1）熟练掌握 评估疾病动物模型中的心血管病理生理学并培养成为 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。 最近从泰珀商学院 MBA 课程毕业，他将通过教学来补充他的培训 他召集了分子药理学、药物发现和心血管生理学方面的课程。 在药物发现、心血管动力学和线粒体生物学领域，形成一个有凝聚力的导师团队 科学咨询委员会将在肺科、过敏科、 匹兹堡大学的重症监护和重症监护，该大学在培训医师科学家和 为他的研究和学术独立之路提供了一流的基础设施。 一氧化碳接触是世界范围内中毒的主要原因，并且没有针对一氧化碳的解毒剂。目前的干预措施 效果有限：需要新的疗法。该提案的中心目标是进一步确定。 并开发 CO 中毒的解毒疗法，目标 1 将侧重于建立 CO- 的机制。 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 Aim 2 将测试重组神经球蛋白在严重 CO 中毒小鼠模型中的功效和安全性。 逆转 CO 毒性引起的分子和心脏功能障碍。目标 3 将寻求识别新的血红素。 含有作为二氧化碳清除剂的分子，采用新的制造工艺和发现分析。 这个提议雄心勃勃，Rose 博士现已在紧张的临床和研究中完成了 MBA 学位 培训展示了他在学术环境中处理多项任务的能力（1）正式培训的结合。 (2) 新颖的研究经验 包括疾病建模、药物开发和发现要素；(3) 经验丰富、多元化的指导； 团队和咨询委员会；（4）匹兹堡大学强大的制度环境将 让罗斯博士成为一名独立研究调查员和学术药物发现领导者。