Chronic Kidney Disease-Induced Defects Initiated by SIRPα

SIRPα 引发的慢性肾脏病引起的缺陷

• 批准号: 10588494
• 负责人: Sandhya S Thomas
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588494
• 关键词: Adipose tissue; Adult; Autophagocytosis; Cachexia; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Cardiomyopathies; Cardiorenal syndrome; Cardiovascular Diseases; Chronic Kidney Failure; Circulation; Complication; Culture Media; Data; Defect; Development; FRAP1 gene; Fibroblasts; General Population; Goals; Growth; Growth Factor; Heart; Heart failure; Impairment; Inflammation; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Kidney Diseases; Knock-out; Knockout Mice; Knowledge; Macrophage; Measures; Mediating; Mediator; Metabolic; Molecular; Mus; Muscle; Myocardial; Myocardial dysfunction; Myocardium; PTPN11 gene; Pathway interactions; Patients; Prevalence; Protein Biosynthesis; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Public Health; Receptor Signaling; Recombinants; Resistance; Role; SHPS-1 protein; Serum; Signal Transduction; Skeletal Muscle; Sulfate; System; Testing; Toxin; Tyrosine; Ubiquitin; Uremia; Veterans; adverse outcome; cell type; heart function; improved; mortality; multicatalytic endopeptidase complex; muscle form; new therapeutic target; novel; potential biomarker; prevent; protein degradation; receptor; receptor binding; receptor function; recruit; response; skeletal muscle wasting; targeted biomarker; therapeutic target; uremic cardiomyopathy

Chronic kidney disease (CKD) is a major public health problem, afflicting an estimated 15% (37 million) of US adults. Among Veterans, the prevalence of CKD is nearly 50% higher than that of the US general population. CKD-associated mortality is significantly higher than that of the general population and worsens with each stage of progressive CKD. The reason for these adverse outcomes is generally attributed to the development of cardiovascular disease and changes in myocardial size. There are several critical gaps in our current knowledge of cardiac remodeling in CKD. Our long term goal is to identify the molecular mechanisms responsible for CKD-induced cardiomyopathy. We have previously identified that signal regulatory protein alpha (SIRPα) is upregulated as a mediator of CKD-induced insulin resistance in skeletal muscles. Specifically, that CKD stimulates inflammation to upregulate SIRPα in skeletal muscles of mice and patients with CKD. Subsequently, SIRPα promotes insulin resistance in skeletal muscles and adipose tissue causing cachexia. CKD stimulates the opposite responses in the heart with increases in myocardial mass. The significance of our proposal is that we provide evidence for a differential role of SIRPα in mediating cachexia in skeletal muscles and adipose tissues while contributing to the development of increased cardiac muscle growth. We predict cardiac remodeling in CKD may be the result of impairments in myocardial insulin/insulin growth factor-1 (IGF1) receptor signaling. CENTRAL HYPOTHESIS: SIRPα behaves as a novel myokine impairing myocardial insulin/IGF1 receptor functions while promoting CKD-induced cardiomyopathy. Guided by strong preliminary data we propose three Specific Aims to characterize the metabolic milieu of CKD and its effects on myocardial mass: (1) Determine if SIRPα exacerbates myocardial insulin/IGF1 receptor signaling in CKD. (2) Identify CKD-specific (i.e. uremia) triggers that cause SIRPα release. (3) Evaluate the anti-proteolytic effects of SIRPα in modulating myocardial protein turnover in CKD. Our goal is to determine if SIRPα interacts with insulin/IGF1 receptor impairing intracellular signaling to promote myocardial growth and cardiac dysfunction. This discovery will stimulate novel targets for therapies to prevent CKD-associated heart failure and potentially improve the lives of Veterans suffering from its deleterious consequences.

慢性肾病 (CKD) 是一个主要的公共卫生问题，估计影响 15% (37 百万）美国成年人中，CKD 患病率比美国高出近 50%。 一般人群的 CKD 相关死亡率显着高于一般人群。 并随着进展性 CKD 的每个阶段而恶化。这些不良结果的原因通常是。 归因于心血管疾病的发展和心肌大小的变化。 我们目前对 CKD 心脏重塑的了解存在几个关键差距。 确定 CKD 诱发的心肌病的分子机制。 我们之前已经发现信号调节蛋白 α (SIRPα) 作为一种上调 具体而言，CKD 会刺激骨骼肌中 CKD 诱导的胰岛素抵抗。 随后，小鼠和 CKD 患者骨骼肌中的炎症上调 SIRPα。 SIRPα 促进骨骼肌和脂肪组织中的胰岛素抵抗，导致 CKD。 随着心肌质量的增加，刺激心脏的相反反应。 我们的建议是，我们为 SIRPα 在介导骨骼恶病质中的不同作用提供证据 肌肉和脂肪组织，同时有助于心肌生长的增加。 我们预测 CKD 中的心脏重塑可能是心肌胰岛素/胰岛素损伤的结果 生长因子-1 (IGF1) 受体信号传导。 中心假设：SIRPα 表现为一种新型肌因子，损害心肌 胰岛素/IGF1受体功能强，同时促进CKD诱发的心肌病。 根据初步数据，我们提出了三个具体目标来描述 CKD 的代谢环境及其 对心肌质量的影响：(1) 确定 SIRPα 是否会恶化心肌胰岛素/IGF1 受体 (2) 识别导致 SIRPα 释放的 CKD 特异性（即尿毒症）触发因素。 SIRPα 在调节 CKD 心肌蛋白周转中的抗蛋白水解作用。 我们的目标是确定 SIRPα 是否与损害细胞内的胰岛素/IGF1 受体相互作用 这一发现将刺激新的促进心肌生长和心脏功能障碍的信号传导。 预防 CKD 相关心力衰竭并可能改善患者生活的治疗目标 退伍军人遭受其有害后果。