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（由申请人提供）：慢性肾脏病（CKD）是一种健康流行病，可增加心血管疾病导致的死亡风险。通过促进心力衰竭，心脏肥大是CKD的重要病理学，并且在达到透析时影响高达90%的患者。成纤维细胞生长因子23（FGF 23）是一种调节磷酸盐稳态的骨分泌激素。血清FGF 23水平在CKD中组成性升高，并且随着患者进展至肾衰竭而持续升高。虽然FGF 23的大量增加有助于维持正常的血清磷酸盐水平，但前瞻性人体研究表明，较高的FGF 23水平与心血管事件和死亡率风险之间存在剂量依赖性相关性。作为一种潜在的机制，我们证明了在一个大型CKD队列中升高的FGF 23与心脏肥大密切相关，并且FGF 23可以在培养的心肌细胞和一系列血清FGF 23升高的动物模型中诱导肥大。我们以前的工作表明，FGF 23过量代表了CKD中病理性心脏肥大的一种新的风险倍增机制。本提案的目的是确定CKD中心脏重塑所需的FGF 23受体以及心肌细胞中的潜在信号机制。我们在异源细胞培养物中的初步数据表明，在四种FGF受体亚型（FGFR 1 -4）中，FGF 23可以特异性地激活FGFR 4，这导致磷脂酶C β（PLC β）的激活。阻断PLC β、钙调磷酸酶或FGFR 4抑制FGF 23诱导的体外心肌细胞肥大生长。与野生型小鼠不同，通过高磷酸盐饮食升高FGFR 4基因敲除小鼠中的FGF 23并不是因为心脏肥大，并且来自这些小鼠的分离的心肌细胞被保护免于FGF 23介导的肥大。在目标1中，我们将确定FGFR 4活化是否足以诱导心脏肥大。我们的初步数据表明，具有FGFR 4功能获得性突变（FGFR 4-G385 R）的已建立的基因敲入小鼠模型在6个月龄时具有肥大，并且我们将分析这些小鼠是否进一步发展心脏损伤，包括心肌细胞凋亡和导致心力衰竭的间质纤维化。此外，我们将分析FGFR 4-G385 R小鼠的心脏重塑是否因压力超负荷或神经内分泌刺激而加剧。目的二：研究FGF 23-FGFR 4介导的心肌肥大的机制。我们推测FGFR 4激活诱导心肌细胞中的钙调神经磷酸酶/NFAT信号传导。在目标3中，我们将分析FGF 23长期升高的动物中病理性心脏重塑是否需要FGFR 4。在概念验证实验中，我们想要确定高度特异性FGFR 4阻断抗体是否减弱CKD啮齿动物模型中的肥大。FGFR 4阻断可能作为一种新的治疗策略，以预防或治疗CKD心力衰竭，并可能更普遍地用于其他形式的心血管疾病患者。