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

项目总结 这份提案描述了一项为期五年的职业发展计划，以帮助大卫·马西亚诺博士 作为一名独立调查员的职业。这个项目建立在马西亚诺博士广泛的 作为一名分子药理学家的背景，为他提供了建立 在细胞外囊泡生物学、活体外科、最先进的成像和IPSC方面的专业知识 探讨治疗肺动脉高压(PAH)的新策略。Dr。 Marciano的主要导师是Michael Snyder博士，他是一位教授，也是遗传学的主席 斯坦福大学医学院和他的共同导师Marlene Rabinovitch博士是一名临床医生 儿科教授，多环芳烃专家。斯奈德博士和拉比诺维奇博士 长期合作，是许多以前的实习生现在建立起来的优秀导师 作为独立调查人员。 Marciano博士K99阶段的研究将集中在支持他对 BMPR2在介导PAH缺氧细胞反应及其功能障碍中的作用具体而言，在AIM中 在Marciano博士的建议中，他试图确定BMPR2富集物的治疗潜力 细胞外小泡(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的建议是，他将研究层流剪应力的影响，摩擦力 EV信号上的血流量。他将应用实时PET成像来跟踪EV的生物分布和 不同细胞扰动对其靶向的影响。在拟议研究的目标3中， Marciano博士将开始研究开发源自自体的“个性化”电动汽车 从患者自己的干细胞中提取，作为减少不良免疫反应的策略。 Marciano博士处于独特的地位，可以利用他在转化医学方面的背景来扩展 令人振奋的初步发现，这项建议建立起来，以确定新的PAH疗法。 这项工作也将为未来的研究提供基础，该研究将由Dr。 马西亚诺作为独立调查员。

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.