A new large pre-clinical model of aging-related heart failure: a platform to develop new therapies for HFpEF

衰老相关心力衰竭的新型大型临床前模型：开发 HFpEF 新疗法的平台

• 批准号: 10750836
• 负责人: Alejandro Roberto Chade
• 金额: $ 45.98万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750836
• 关键词: 10 year old; Abate; Address; Adolescent; Adult; Affect; Age; Aging; Angiogenic Factor; Biochemical; Biodistribution; Biological; Blood Vessels; Cardiac; Cardiology; Cardiovascular system; Chronic Kidney Failure; Complex; Data; Deterioration; Development; Disease; Dose; Down-Regulation; Drug Delivery Systems; Drug Kinetics; EFRAC; Echocardiography; Elastin; Elderly; Epigenetic Process; Family suidae; Female; Fostering; Foundations; Functional disorder; Future; Genes; Goals; Heart; Heart Abnormalities; Heart failure; Hospitalization; Human; Hypertension; Immunoprecipitation; Kidney; Knowledge; Left Ventricular Remodeling; Libraries; Longitudinal Studies; Magnetic Resonance; Messenger RNA; MicroRNAs; Microcirculation; Mission; Modeling; Modification; Molecular; Molecular Weight; Myocardial dysfunction; Obesity; Organ; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Process; Published Database; Qualifying; Research; Risk Factors; Role; Signal Transduction; Testing; Therapeutic; Time; United States National Institutes of Health; VEGFA gene; Vascular Endothelial Growth Factors; aged; bench to bedside; comorbidity; delivery vehicle; effective therapy; experimental study; heart function; innovation; mRNA sequencing; male; mortality; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; polypeptide; preservation; sex; therapeutic angiogenesis; transcriptomics; vascular endothelial dysfunction

Heart failure with preserved ejection fraction (HFpEF) is the predominant form of HF in the elderly and one of the largest unmet needs in cardiology. Cardiovascular aging is a complex process crafted by risk factors, biological variables (e.g., sex), and prevalent comorbidities like chronic kidney disease (CKD) that contribute to the development of HF. CKD is a disease that affects almost 40% of US adults ≥65 years and HFpEF is present in over 50% of CKD patients. However, limited knowledge about the impact of aging on CKD-HFpEF pathophysiology and the lack of models calls for efforts for new strategies to counteract the deterioration of cardiac function in CKD. We are uniquely qualified to address these needs since 1) We developed in juvenile pigs a model of CKD with left ventricular remodeling and diastolic dysfunction that recapitulates human HFpEF. 2) Cardiac dysfunction and remodeling in the CKD-HFpEF model show a significant reduction in cardiac vascular endothelial growth factor (VEGF) expression, in line with prior research on aging hearts. 3) We developed drug-delivery vectors based on elastin-like polypeptides (ELP) and showed their efficacy to deliver therapeutics to the kidney, including VEGF. In addition, we built a library of ELPs that based on their molecular weight can target different organs, including the heart. However, ELPs have never been used for cardiac therapies. 4) Unbiased analysis (published database) in the juvenile CKD-HFpEF model showed that cardiac abnormalities are associated with cardiac epigenetic and miRNA modifications of VEGF-related genes, altered angiogenic signaling, and cardiac microvascular rarefaction. The premise underlying this innovative R21 proposal is multi-fold: 1) We will develop the first model of HFpEF in normally aged pigs to recapitulate the phenotype of aging HFpEF in humans. This model will also foster the study of age and sex as biological variables in an unprecedented fashion. 2) We will test, for the first time, a therapeutic strategy to abate cardiac microvascular rarefaction, an important determinant of cardiac dysfunction in HFpEF by targeting VEGF angiogenic signaling using ELP-based therapeutic angiogenesis. Finally, we will set the foundation for new therapies in aging HFpEF by defining mechanisms of VEGF downregulation driven by cardiac microRNA (miRNA) and epigenetic modulation. Aim 1: Development of the first model of HFpEF in a normally aged swine. These studies will identify pathological pathways in aging HFpEF and offer a new suitable platform to guide the development of new therapeutic strategies in a translational fashion. Aim 2: Downregulation of VEGF signaling leads to cardiac microvascular rarefaction and HFpEF in aging. These studies will mechanistically define the role of VEGF in the normally aged heart and build the foundation for a new targeted therapy in aging HFpEF. By discerning mechanisms of altered cardiac signaling of VEGF-related genes, we will set the stage to explore new treatments. This proposal assures innovation by both developing a new model of aging HFpEF and by establishing the mechanistic foundation for new therapeutic strategies for HFpEF, which will result in a paradigm shift that aligns with the bench-to-bedside strategic mission of the NIH-NIA.

心力衰竭，保留的射血分数（HFPEF）是HF的主要形式，其中之一是 心脏病学中最大的未满足需求。心血管衰老是一个由风险因素，生物学的复杂过程 变量（例如性别）和普遍的合并症，例如慢性肾脏病（CKD） HF的发展。 CKD是一种影响近40％的美国成年人≥65岁的疾病，HFPEF存在于 超过50％的CKD患者。但是，关于衰老对CKD-HFPEF病理生理学的影响有限 缺乏模型需要努力制定新的策略来抵消CKD中心脏功能恶化的努力。 自从1）我们在少年猪中开发的CKD模型以来，我们具有独特的资格来满足这些需求 概括人HFPEF的心室重塑和舒张功能障碍。 2）心脏功能障碍和 CKD-HFPEF模型中的重塑显示心脏血管内皮生长因子的显着降低 （VEGF）表达与先前对衰老心脏的研究相一致。 3）我们基于 弹性蛋白样的多肽（ELP），并显示了其为包括VEGF在内的肾脏提供治疗的效率。 此外，我们建立了一个基于它们的分子量的ELP库​​，可以针对不同的器官，包括 心。但是，ELP从未用于心脏疗法。 4）无偏分析（已发布数据库） 少年CKD-HFPEF模型表明，心脏异常与心脏表观遗传学和 VEGF相关基因的miRNA修饰，血管生成信号的改变和心脏微血管稀疏。 此创新的R21提案的前提是多重的：1）我们将开发HFPEF的第一个模型 在正常老化的猪中，可以概括人类衰老的HFPEF的表型。该模型还将促进 以前所未有的方式研究年龄和性别作为生物学变量。 2）我们将首次测试 减轻心脏微血管罕见的治疗策略，这是心脏功能障碍的重要决定因素 通过使用基于ELP的治疗性血管生成的VEGF血管生成信号传导来靶向HFPEF。最后，我们将设置 通过定义由心脏驱动的VEGF下调的机制，用于衰老HFPEF的新疗法基础 microRNA（miRNA）和表观遗传调节。 AIM 1：通常在正常的HFPEF中开发 老化的猪。 这些研究将确定HFPEF衰老的病理途径，并提供新的合适平台 以转化方式指导新的治疗策略的制定。 目标2：VEGF的下调 信号传导导致心脏微血管稀疏和衰老中的HFPEF。 这些研究将机械化 定义VEGF在正常老化的心脏中的作用，并为在衰老中进行新的靶向疗法奠定基础 HFPEF。通过辨别与VEGF相关基因的心脏信号改变的机制，我们将把阶段设置为 探索新的治疗方法。该提案通过开发新的老化HFPEF模型来实现创新 并通过为HFPEF建立新的治疗策略的机械基础，这将导致 在与NIH-NIA的基准对床的战略任务相吻合的范式转变中。