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.

射血分数保留的心力衰竭（HFpEF）是老年人心力衰竭的主要形式，也是最常见的心衰类型之一。 心脏病学中最大的未满足需求心血管衰老是一个由危险因素、生物因素造成的复杂过程。 变量（例如性别）和常见的合并症（例如慢性肾脏病（CKD））会导致 CKD 是一种影响 40% ≥ 65 岁美国成年人的疾病，HFpEF 存在于 然而，关于衰老对 CKD-HFpEF 病理生理学影响的了解有限。 由于模型的缺乏，需要采取新的策略来对抗 CKD 中心脏功能的恶化。 我们具有独特的资格来满足这些需求，因为 1) 我们在幼猪中开发了左左 CKD 模型 心室重构和舒张功能障碍，概括了人类 HFpEF 2) 心脏功能障碍和 CKD-HFpEF模型中的重塑显示心肌血管内皮生长因子显着减少 (VEGF) 表达，与先前对衰老心脏的研究一致 3) 我们开发了基于的药物递送载体。 弹性蛋白样多肽 (ELP) 并显示出它们向肾脏输送治疗药物的功效，包括 VEGF In。 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 然而，ELP 从未用于心脏治疗 4) 无偏见分析（已发表的数据库）。 青少年 CKD-HFpEF 模型表明心脏异常与心脏表观遗传和 VEGF 相关基因的 miRNA 修饰、血管生成信号传导改变和心脏微血管稀疏。 这一创新 R21 提案的前提是多方面的：1) 我们将开发第一个 HFpEF 模型 该模型也将在正常衰老的猪中重现人类衰老 HFpEF 的表型。 以前所未有的方式研究年龄和性别作为生物变量 2) 我们将首次测试一个。 减轻心脏微血管稀疏的治疗策略，这是心脏功能障碍的重要决定因素 HFpEF 通过使用基于 ELP 的治疗性血管生成来靶向 VEGF 血管生成信号。 通过定义心脏驱动的 VEGF 下调机制，为衰老 HFpEF 的新疗法奠定基础 microRNA (miRNA) 和表观遗传调节。 目标 1：在正常情况下开发第一个 HFpEF 模型 老猪。 这些研究将确定衰老 HFpEF 的病理途径，并提供一个新的合适平台 以转化方式指导新治疗策略的开发。 目标 2：下调 VEGF 信号传导导致衰老过程中心脏微血管稀疏和 HFpEF。 这些研究将机械地 确定 VEGF 在正常衰老心脏中的作用，并为新的衰老靶向治疗奠定基础 通过辨别 VEGF 相关基因的心脏信号传导改变的机制，我们将为 HFpEF 奠定基础。 该提案通过开发老化 HFpEF 的新模型来确保创新。 并为 HFpEF 的新治疗策略奠定机制基础，这将导致 与 NIH-NIA 从实验室到临床的战略使命相一致的范式转变。