Exosome Therapeutics to Dissect HFpEF Mechanisms

外泌体疗法剖析 HFpEF 机制

基本信息

批准号：
10427452
负责人：
EDUARDO MARBAN
金额：
$ 83.44万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427452
关键词：
Animal Model Anti-Inflammatory Agents Arrhythmia Attenuated Back Benchmarking Biopsy Biopsy Specimen Cell Therapy Cells Chemicals Collagen Complex Control Groups Data Disease EFRAC Exposure to FRAP1 gene Failure Family suidae Fibrosis Genetic Transcription Goals Heart Heart failure Histologic Human Inflammation Intervention Mediating Medical Device Methods MicroRNAs Mining Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Myocardial Pathogenesis Pathway interactions Patients Pharmacology Phenotype Post-Translational Protein Processing Proteins Proteome Proteomics RNA RNA analysis Rattus Reporting Rodent Sorting - Cell Movement Techniques Testing Therapeutic Tissues Translations Treatment Efficacy Treatment Failure Untranslated RNA Ventricular base cardioprotection comorbidity comparative efficacy cost design disease phenotype exosome extracellular vesicles improved in vivo mechanical properties mortality mouse model novel novel strategies novel therapeutics porcine model preservation response single-cell RNA sequencing targeted treatment therapeutic candidate transcriptome sequencing transcriptomics treatment response

项目摘要

PROJECT SUMMARY No effective pharmacological or medical device interventions are available to treat heart failure with preserved ejection fraction (HFpEF). We have pioneered the concept of cell therapy for HFpEF: Cardiosphere-derived cells (CDCs) dramatically improve diastolic function and reduce arrhythmias, while attenuating fibrosis and inflammation. Most, if not all, of these beneficial effects are mediated by exosomes secreted by CDCs (CDCEXO). Here we seek to establish detailed molecular signatures of HFpEF; to use those molecular signatures as roadmaps to identify key, potentially causal pathways by dissecting the responses to CDCEXO; and to discover novel defined molecular entities, based on CDCEXO cargo, with disease-modifying bioactivity in HFpEF. Our hypotheses, backed by strong preliminary data, are: • Underlying HFpEF are bewilderingly extensive changes in myocardial transcriptomics and proteomics. Sorting causal from associative changes presents a major challenge, but it is doable. • A subset of these HFpEF-related proteome changes are reversed by CDCs or CDCEXO and some correlated to the reversal of the key functional abnormalities of HFpEF. We posit that focusing on CDCEXO-responsive pathways will facilitate the search for causal abnormalities, enabling targeted hypothesis testing. • By mining the RNA and protein contents of CDCEXO, we have the potential to pinpoint defined factors which have disease-modifying bioactivity in HFpEF. Such defined factors may themselves be viable therapeutic candidates, or can inspire the creation of new chemical entities as therapeutic candidates. The overall goal of this proposal is to understand better the pathogenesis of HFpEF, and to develop novel cell- free approaches to treat this disease. Three aims are proposed. In Aim 1 we will perform and analyze tissue and single cell transcriptomics and proteomics (including numerous protein post-translational modifications) of HFpEF, in three different models (pig, mouse and rat) that represent different comorbidities and compare their disease signature to those in human HFpEF heart tissue. Commonalities in the OMICS responses among species will help distinguish causal versus associative pathways in HFpEF pathogenesis. Aim 2 will analyze molecular signatures of therapeutic efficacy by comparing transcriptomics and proteomics with and without exposure to CDCEXO. Because CDCs and their exosomes strikingly reverse the HFpEF phenotype, identification of CDCEXO-induced molecular changes will further refine pathway prioritization in terms of causal versus associative. Here we will study ventricular tissue and single cells from rat, mouse and pig models of HFpEF (and controls), with and without in vivo exposure to CDCEXO. In Aim 3 we will mine CDCEXO cargo to identify critical factors underlying disease-modifying bioactivity in a rat model of HFpEF. This will allow us to define and/or create specific molecular entities (either RNA species or proteins) that may be preferable to complex biologicals (cells, exosomes) in terms of mechanistic discreteness, ease of manufacturing, and therapeutic consistency.

项目摘要没有有效的药物或医疗设备干预措施可用于治疗心力衰竭射血分数（HFPEF）。我们已经开创了HFPEF细胞疗法的概念：心圈衍生的细胞（CDC）显着提高舒张功能并减少心律不齐，同时减弱纤维化和炎。这些有益作用中的大多数（如果不是全部）是由CDC分泌（CDCEXO）分泌的外泌体介导的。在这里，我们试图建立HFPEF的详细分子特征。将这些分子特征用作路线图通过解剖CDCEXO的响应来识别钥匙，潜在的因果途径；并发现基于CDCEXO货物的新颖定义的分子实体，在HFPEF中具有疾病改良的生物活性。我们的在强大初步数据的支持下，假设是： •基础HFPEF是心肌转录组学和蛋白质组学的巨大变化。排序关联变化的因果带来了一个重大挑战，但这是可行的。 •这些与HFPEF相关的蛋白质组变化的子集由CDC或CDCEXO逆转，并且有些相关逆转HFPEF的关键功能异常。我们积极关注CDCEXO响应性途径将有助于寻找因果异常，从而实现目标假设检验。 •通过挖掘CDCEXO的RNA和蛋白质含量，我们有可能查明定义因素，这些因素在HFPEF中具有疾病改良的生物活性。这种定义的因素本身可能是可行的疗法候选人，或者可以激发新化学实体作为治疗候选者的创建。该提案的总体目标是更好地了解HFPEF的发病机理，并发展出新的细胞 - 免费治疗这种疾病的方法。提出了三个目标。在AIM 1中，我们将执行和分析组织和单细胞转录组学和蛋白质组学（包括众多蛋白质后翻译修饰） HFPEF，三种不同的模型（猪，小鼠和大鼠），代表不同的合并症并比较它们疾病签名到人类HFPEF心脏组织中的疾病。 OMICS回答的共同点 AIM 2将分析通过有或没有的转录组学和蛋白质组学，有或没有暴露于CDCEXO。因为CDC及其外泌体显着扭转了HFPEF表型，因此识别 CDCEXO诱导的分子变化将进一步完善途径优先考虑因果与协会。在这里，我们将研究HFPEF的大鼠，小鼠和猪模型的心室组织和单细胞（和对照），有或没有体内暴露于CDCEXO。在AIM 3中，我们将开采CDCEXO货物以识别关键 HFPEF大鼠模型中疾病改良生物活性的基本因素。这将使我们能够定义和/或创建特定的分子实体（RNA物种或蛋白质）可能比复杂的生物制剂（细胞，外泌体）就机械离散性，易于制造和治疗性一致性而言。