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.

射血分数正常的心力衰竭（HFpEF）是老年人HF的主要形式，也是老年人心力衰竭的主要原因之一。 最大的未满足需求。心血管老化是一个复杂的过程，由危险因素、生物学因素、 变量（例如，性别），以及常见的合并症，如慢性肾脏疾病（CKD），这些合并症导致 HF的发展。慢性肾病是一种影响近40% ≥65岁的美国成年人的疾病，HFpEF存在于 超过50%的CKD患者。然而，关于衰老对CKD-HFpEF病理生理学影响的知识有限， 缺乏模型需要努力寻找新的策略来对抗CKD患者心脏功能的恶化。 我们是唯一有资格满足这些需求，因为1）我们在幼猪中开发了CKD模型， 心室重塑和舒张功能障碍，重现人类HFpEF。2)心功能不全及 CKD-HFpEF模型中的重构显示心脏血管内皮生长因子 （VEGF）表达，与先前对衰老心脏的研究一致。3)我们开发了药物传递载体， 弹性蛋白样多肽（ELP），并显示出它们将治疗剂（包括VEGF）递送至肾脏的功效。在 此外，我们建立了一个ELP库，根据其分子量可以靶向不同的器官，包括 心然而，ELP从未用于心脏治疗。4)无偏倚分析（已发表数据库） 幼年CKD-HFpEF模型显示心脏异常与心脏表观遗传相关， 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 这项创新的R21提案的前提是多方面的：1）我们将开发HFpEF的第一个模型 在正常年龄的猪中重现人类中老化HFpEF的表型。这一模式还将促进 以前所未有的方式研究年龄和性别作为生物变量。2)我们将首次测试 减轻心脏微血管稀疏的治疗策略，心脏微血管稀疏是心脏功能障碍的重要决定因素， HFpEF通过使用基于ELP的治疗性血管生成靶向VEGF血管生成信号传导。最后，我们将设置 通过定义心脏驱动的VEGF下调机制为老年HFpEF的新疗法奠定基础 microRNA（miRNA）和表观遗传调节。 目的1：在正常人中开发第一个HFpEF模型 老猪 这些研究将确定衰老HFpEF的病理途径，并提供新的合适的平台 以转化的方式指导新的治疗策略的发展。 目的2：下调VEGF 信号传导导致心脏微血管稀疏和衰老中的HFpEF。 这些研究将机械地 明确VEGF在正常衰老心脏中的作用，为衰老的新靶向治疗奠定基础 HFpEF。通过识别血管内皮生长因子相关基因改变心脏信号传导的机制，我们将为以下工作奠定基础 探索新的治疗方法该提案通过开发一种新的老化HFpEF模型来确保创新 并通过建立HFpEF新治疗策略的机制基础，这将导致 这是一个与NIH-NIA从实验室到床边的战略使命相一致的范式转变。