Therapeutic Rescue of a Deficient BMPR2 Hypoxic Response in Pulmonary Arterial Hypertension

肺动脉高压患者 BMPR2 缺陷缺氧反应的治疗性挽救

• 批准号: 10657009
• 负责人: David P Marciano
• 金额: $ 24.9万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657009
• 关键词: Animal Model; Animals; Autologous; BMPR2 gene; Biodistribution; Biogenesis; Biology; Blood flow; CRISPR correction; Candidate Disease Gene; Cardiovascular system; Cell Hypoxia; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; DNA Sequence Alteration; Dependence; Development; Disease; Disease Progression; Drug Kinetics; Endothelial Cells; Environment; Foundations; Friction; Functional disorder; Future; Gene Expression Profile; Genetic; Goals; Heritability; Hypoxia; ITGB4 gene; Image; In Vitro; Inflammatory; Institution; Integrin beta4; Investigation; Knockout Mice; Link; Lung; Mediating; Membrane Proteins; Mentors; Messenger RNA; Modeling; Molecular; Mutation; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Penetrance; Phase; Phenotype; Physiological; Positioning Attribute; Positron-Emission Tomography; Production; Program Development; Proteins; Reporting; Research; Research Personnel; Role; Signal Transduction; Stress; Systems Biology; Testing; Therapeutic; Therapeutic Index; Training; Transgenic Organisms; Universities; Work; base; biological adaptation to stress; bone loss; career; career development; clinical application; design; exosome; extracellular vesicles; gene environment interaction; human disease; hypertension treatment; immunogenicity; immunoreaction; improved; in vivo; induced pluripotent stem cell; innovation; multiple omics; mutant; novel therapeutic intervention; pediatric department; prevent; professor; programs; pulmonary arterial hypertension; pulmonary artery endothelial cell; response; shear stress; stem cells; therapy development; translational medicine; vesicular release

PROJECT SUMMARY This proposal describes a five-year career development program to prepare Dr. David Marciano for a career as an independent investigator. This program builds on Dr. Marciano’s extensive background as a molecular pharmacologist by providing him with the training to establish expertise in extracellular vesicle biology, in vivo surgery, state-of-the-art imaging and iPSC to investigate new therapeutic strategies to treat pulmonary arterial hypertension (PAH). Dr. Marciano’s primary mentor is Dr. Michael Snyder, a Professor and chair of the Genetics department at Stanford University and his Co-mentor Dr. Marlene Rabinovitch is a clinical professor in the pediatrics department and expert in PAH. Drs. Snyder and Rabinovitch have a long standing collaboration and are excellent mentors with many former trainees now established as independent investigators. The K99 phase of Dr. Marciano’s studies will focus on supporting his investigation into the role of BMPR2 in mediating the hypoxic cellular response and its dysfunction in PAH. Specifically, in AIM 1 of Dr. Marciano’s proposal he seeks to determine the therapeutic potential of BMPR2 enriched extracellular vesicles (EV) in reversing disease progression. The therapeutic application of EV is an emerging field that Dr. Marciano is being trained in as a future leader. In AIM 2 of Dr. Marciano’s proposal he will investigate the effect of laminar shear-stress, the frictional force of blood flow on EV signaling. He will apply live PET imaging to track the bioidistriubtion of EV and the effect of different cellular perturbations on their targeting. In Aim 3 of the proposed studies, Dr. Marciano will initiate studies towards the development of autologous ‘personalized’ EV derived from a patient’s own stem cells as a strategy to reduce adverse immune reactions. Dr. Marciano is uniquely positioned to leverage his background in translational medicine to extend the exciting preliminary findings from which this proposal builds to identify new PAH therapies. This work will also provide the foundation for future studies, which will be carried out by Dr. Marciano as an independent investigator.

项目摘要 该提案描述了一个为期五年的职业发展计划，以准备大卫马西亚诺博士 作为一名独立调查员该计划建立在Marciano博士广泛的 作为一个分子药理学家的背景，为他提供培训， 在细胞外囊泡生物学、体内手术、最先进的成像和iPSC方面的专业知识， 研究治疗肺动脉高压（PAH）的新治疗策略。博士 Marciano的主要导师是Michael Snyder博士，他是遗传学教授和主席。 斯坦福大学的博士和他的共同导师Marlene Rabinovitch博士是一位临床 儿科教授，PAH专家。斯奈德医生和拉宾诺维奇医生 长期的合作，是优秀的导师，许多前学员现在建立 作为独立调查员 Marciano博士研究的K99阶段将重点支持他对以下因素作用的研究： BMPR2在肺动脉高压中介导的细胞缺氧反应及其功能障碍具体而言，在AIM Marciano博士的建议之一，他试图确定BMPR2富集的治疗潜力 细胞外囊泡（EV）逆转疾病进展。EV的治疗应用是 这是一个新兴的领域，马西亚诺博士正在接受培训，成为未来的领导者。在博士的AIM 2中。 Marciano的建议，他将研究层流剪应力的影响， 血流对EV信号的影响他将应用实时PET成像来跟踪EV的生物识别， 不同的细胞扰动对其靶向的影响。在拟议研究的目标3中， 博士Marciano将开始研究开发自体“个性化”EV衍生物 从患者自身的干细胞中提取，作为减少不良免疫反应的策略。 博士Marciano具有独特的优势，可以利用他在转化医学方面的背景， 令人兴奋的初步研究结果，该提案建立在确定新的PAH治疗方法的基础上。 这项工作也将为将来的研究提供基础，这将由Dr。 马西亚诺作为独立调查员。