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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

基本信息

批准号：
10677852
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
项目类别：
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/10677852
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 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 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 biological adaptation to stress bone loss career career development clinical application design efficacy evaluation 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

项目摘要

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.

项目总结