ACTIVATION OF CARDIAC FGFR4 CAUSES LEFT VENTRICULAR HYPERTROPHY

心脏 FGFR4 的激活导致左心室肥大

• 批准号: 8945074
• 负责人: Christian Faul
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8945074
• 关键词: Adrenergic Agents; Affect; Age; Age-Months; Angiotensin II; Angiotensin II Receptor; Animal Model; Animals; Apoptosis; Attenuated; Binding; Blocking Antibodies; Blood Pressure; Calcineurin; Calcium; Calmodulin; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Catheterization; Cell Culture Techniques; Cell Surface Receptors; Cells; Cessation of life; Chronic; Chronic Kidney Failure; Data; Development; Dialysis procedure; Diet; Disease; Dose; Drug Targeting; Echocardiography; Epidemic; Event; FGFR1 gene; FGFR4 gene; Fibroblast Growth Factor Receptors; Fibrosis; G-Protein-Coupled Receptors; Genetic Models; Goals; Growth; Health; Heart; Heart Hypertrophy; Heart failure; Histopathology; Homeostasis; Hormones; Human; Hypertrophy; In Vitro; Individual; Infusion procedures; Injury; Isoproterenol; Kidney Diseases; Kidney Failure; Knock-in Mouse; Knockout Mice; Left; Left Ventricular Hypertrophy; Mammals; Mediating; Mediator of activation protein; Modeling; Mus; Muscle Cells; Mutation; Neonatal; Nephrectomy; Neurosecretory Systems; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Phospholipase; Phospholipase C; Phosphorylation; Play; Prevalence; Process; Protein Isoforms; Protein phosphatase; Rattus; Receptor Protein-Tyrosine Kinases; Recombinant Fibroblast Growth Factor; Regulation; Risk; Rodent Model; Role; Series; Serum; Signal Pathway; Signal Transduction; Stimulus; Stress; Testing; Time; Translating; Ventricular; Wild Type Mouse; Work; adrenergic; bone; cardiovascular injury; cardiovascular risk factor; cohort; constriction; coronary fibrosis; feeding; fibroblast growth factor 23; gain of function; gain of function mutation; in vivo; inorganic phosphate; interstitial; mortality; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; nuclear factors of activated T-cells; pressure; prevent; prospective; public health relevance; receptor; research study; response; therapeutic target; translational study

 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to cardiovascular disease. By promoting heart failure, cardiac hypertrophy is an important pathology in CKD and affects up to 90% of patients by the time they reach dialysis. Fibroblast growth factor 23 (FGF23) is a bone-secreted hormone that regulates phosphate homeostasis. Serum FGF23 levels are constitutively elevated in CKD and continuously rise as patient's progress to renal failure. While this massive increase in FGF23 helps to maintain normal serum phosphate levels, prospective human studies demonstrated a dose-dependent association between higher FGF23 levels and greater risks of cardiovascular events and mortality. As a potential mechanism, we demonstrated that elevated FGF23 is strongly associated with cardiac hypertrophy in a large CKD cohort, and that FGF23 can induce hypertrophy in cultured cardiac myocytes and in a series of animal models with elevated serum FGF23. Our previous work suggests that FGF23 excess represents a novel, risk-multiplying mechanism of pathological cardiac hypertrophy in CKD. The purpose of this proposal is to identify the FGF23 receptor that is required for cardiac remodeling in CKD and the underlying signal mechanism in cardiac myocytes. Our preliminary data in heterologous cell cultures indicate that of the four FGF receptor isoforms (FGFR1-4), FGF23 can specifically activate FGFR4 which results in the activation of phospholipase C (PLC). Blockade of PLC, calcineurin or FGFR4 inhibits FGF23-induced hypertrophic growth of cardiac myocytes in vitro. Different from wild type mice, elevating FGF23 in global FGFR4 knock-out mice by high phosphate diet does not because cardiac hypertrophy, and isolated cardiac myocytes from these mice are protected from FGF23-mediated hypertrophy. In Aim 1 we will determine if FGFR4 activation is sufficient to induce cardiac hypertrophy. Our preliminary data indicate that an established knock-in mouse model with an FGFR4 gain-of- function mutation (FGFR4-G385R) has hypertrophy at 6-months of age, and we will analyze if these mice develop further cardiac injury including myocyte apoptosis and interstitial fibrosis leading to heart failure. Furthermore, we will analyze if cardiac remodeling in FGFR4-G385R mice is exacerbated in response to pressure overload or neuroendocrine stimulation. In Aim 2 we want to study the mechanism of FGF23-FGFR4 mediated hypertrophy. We postulate that FGFR4 activation induces calcineurin/NFAT signaling in cardiac myocytes. In Aim 3 we will analyze if FGFR4 is required for pathological cardiac remodeling in animals with prolonged FGF23 elevations. In a proof-of-concept experiment we want to determine if a highly specific FGFR4 blocking antibody attenuates hypertrophy in a rodent model of CKD. FGFR4 blockade might serve as a novel therapeutic strategy to prevent or treat heart failure in CKD, and potentially more generally in patients with other forms of cardiovascular disease.

 描述(申请人提供)：慢性肾脏疾病(CKD)是一种健康流行病，会增加因心血管疾病而死亡的风险。通过促进心力衰竭，心肌肥厚是CKD的一种重要病理，在患者达到透析时影响高达90%的患者。成纤维细胞生长因子23(FGF23)是一种调节磷酸盐稳态的骨分泌激素。CKD患者血清FGF23水平呈结构性升高，并随着患者进展为肾功能衰竭而持续升高。虽然FGF23的大量增加有助于维持正常的血磷水平，但前瞻性的人类研究表明，较高的FGF23水平与更高的心血管事件和死亡风险之间存在剂量依赖性的关联。作为一个潜在的机制，我们证明了在一个大的CKD队列中，FGF23升高与心肌肥大密切相关，并且在培养的心肌细胞和一系列血清FGF23升高的动物模型中，FGF23可以诱导心肌细胞肥大。我们以前的工作表明，FGF23的过度表达代表了CKD病理性心肌肥厚的一种新的、风险倍增的机制。本研究的目的是确定慢性肾脏病心脏重构所需的FGF23受体及其在心肌细胞中的潜在信号机制。我们在异种细胞培养中的初步数据表明，在四种成纤维细胞生长因子受体亚型(FGFR1-4)中，FGF23可以特异性地激活FGFR4，从而导致磷脂酶C(PLC)的激活。阻断PLC、钙调神经磷酸酶或FGFR4可抑制FGF23诱导的心肌细胞肥大生长。与野生型小鼠不同，高磷饮食上调FGFR4基因敲除小鼠的FGF23不是因为心肌肥大，而是这些小鼠分离的心肌细胞受到FGF23介导的肥大的保护。在目标1中，我们将确定FGFR4的激活是否足以诱导心肌肥厚。我们的初步数据表明，已建立的带有FGFR4功能获得突变的敲入小鼠模型(FGFR4-G385R)在6个月龄时肥大，我们将分析这些小鼠是否会进一步发展心脏损伤，包括心肌细胞凋亡和间质纤维化导致心力衰竭。此外，我们将分析压力超负荷或神经内分泌刺激是否会加剧FGFR4-G385R小鼠的心脏重构。目的2研究FGF23-FGFR4介导的心肌肥大机制。我们推测FGFR4激活可诱导心肌细胞钙调神经磷酸酶/NFAT信号转导。在目标3中，我们将分析在FGF23升高延长的动物的病理性心脏重塑中是否需要FGFR4。在一项概念验证实验中，我们想要确定一种高度特异的FGFR4阻断抗体是否能减轻CKD啮齿动物模型的肥大。阻断FGFR4可能作为一种新的治疗策略来预防或治疗CKD的心力衰竭，并有可能更广泛地用于其他形式的心血管疾病患者。