Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma

定义肾糖异生在肾细胞癌中的作用

• 批准号: 10360766
• 负责人: Rachel Jamison Perry
• 金额: $ 44.47万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360766
• 关键词: Acetyl Coenzyme A; Adrenergic Agents; Adrenergic Receptor; Affect; Automobile Driving; Cessation of life; Chronic; Chronic Kidney Failure; Clinical Trials; Complement; Data; Diabetes Mellitus; Dwarfism; Enzymes; Genetic; Genetic Predisposition to Disease; Gluconeogenesis; Glucose; Glycolysis; Gold; Homeobox; Human; Impairment; Infusion procedures; Kidney; Kidney Neoplasms; Link; Lipolysis; Liver; Measures; Metabolic; Metabolic stress; Metabolism; Methodology; Methods; Modeling; Mus; Obesity; Organ; Pathogenesis; Pathway interactions; Pharmacology; Pilot Projects; Play; Process; Prognosis; Proteins; Pyruvate Carboxylase; Rattus; Regulation; Renal Adenoma; Renal Cell Carcinoma; Renal carcinoma; Research Personnel; Risk; Rodent; Role; Signal Transduction; Starvation; Techniques; Testing; Time; Tissues; Tracer; Tumor Markers; United States; awake; clinical development; clinical investigation; fibroblast growth factor 21; genetic approach; glucose metabolism; glucose production; glucose uptake; in vivo; inhibitor; mouse model; neutralizing antibody; novel; oxidation; therapeutic target; tumor; tumor growth; tumor metabolism; tumor progression

Project Summary Renal cell carcinoma is the most common primary kidney cancer, representing 90-95% of primary renal neoplasms. Obesity and diabetes are associated with an increased risk of renal cell carcinoma, but the mechanisms by which systemic metabolic changes promote tumor progression are unknown. Although its reputation as a glucose-producing organ has been dwarfed by that of the liver over the years, the kidney possesses the same complement of gluconeogenic enzymes as the liver – with a higher concentration of gluconeogenic proteins per gram of tissue in the kidney, suggesting that its gluconeogenic capacity may even exceed the liver's. Glucose is well-known to be a crucial substrate for tumor growth; given the gluconeogenic activity of the kidney, it is likely that increased renal gluconeogenesis may fuel tumor growth. However, this phenomenon, and its mechanistic explanation, remains to be explored. We have recently found that fibroblast growth factor-21 (FGF-21) promotes renal gluconeogenesis during starvation by activating intrarenal lipolysis through a 2-adrenergic pathway, thereby activating pyruvate carboxylase flux in healthy rodents. Therefore, this proposal will test the Overarching Hypothesis that in renal cell carcinoma, increased FGF-21 acts through a similar mechanism to promote intrarenal lipolysis, pyruvate carboxylase activity, and as a result, gluconeogenesis, and that this increased renal glucose supply fuels tumor growth. We will also examine the utility of an FGF-21 neutralizing antibody against mice genetically prone to renal cell carcinoma, which we anticipate will reduce renal gluconeogenesis and renal cell carcinoma progression. If the hypotheses are confirmed, these data would identify FGF-21 – which is already being targeted in advanced clinical trials for metabolism- and diabetes-related indications – as a potential therapeutic target in renal cell carcinoma.

项目摘要 肾细胞癌是最常见的原发性肾癌，占原发性肾脏的90-95％ 肿瘤。肥胖和糖尿病与肾细胞癌的风险增加有关，但 全身代谢变化促进肿瘤进展的机制尚不清楚。虽然它是 多年来，作为产生葡萄糖的器官的声誉已被肝脏的声誉相形见war。 具有与肝脏相同的谷杆发育酶的完成 - 浓度更高 肾脏中每克组织的糖原蛋白 超过肝脏。葡萄糖众所周知，是肿瘤生长的关键底物。给定糖原 肾脏的活性，肾脏糖异生的增加可能会促进肿瘤的生长。但是，这个 现象及其机械解释仍有待探索。我们最近发现成纤维细胞 生长因子21（FGF-21）通过激活培养质脂解促进饥饿期间肾糖异生 通过2-肾上腺素能途径，从而在健康啮齿动物中激活丙酮酸羧化酶通量。所以， 该提案将检验以下总体假设，即在肾细胞癌中，FGF-21 ACT增加 通过类似的机制来促进内脂解，丙酮酸羧化酶活性，结果 糖异生，并且增加了肾脏葡萄糖供应为肿瘤的生长增添。我们还将检查 FGF-21中和针对小鼠的抗体的效用，易于肾细胞癌，我们 预期将减少肾糖异生和肾细胞癌的进展。如果假设是 确认，这些数据将识别FGF-21 - 这已经在高级临床试验中针对 代谢和糖尿病相关的适应症 - 作为肾细胞癌的潜在治疗靶标。