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The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma

The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma
6-磷酸葡萄糖酶在肝细胞癌中的作用
批准号:
10153987
负责人:
Sherwin Kelekar
金额:
$3.65万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-02-03 至 2025-02-02

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中文摘要
翻译
项目摘要 虽然肝细胞癌(HCC)是肝癌的最常见形式,但很少有治疗方法, 能有效治疗这种恶性疾病只有不到10%的HCC患者存活 5年,重要的是要确定其他治疗漏洞。代谢改变是 HCC发病机制,并代表可能揭示HCC中的责任的靶点。葡萄糖-6-磷酸酶(G6 PC) 在HCC中反复下调,并且这种下调的幅度与患者结果相关。 HCC的测序研究揭示,体细胞突变发生在这些恶性肿瘤的子集中。额外 G6 PC参与HCC的证据来自1a型糖原累积病(GSD 1a),其中 G6 PC中的生殖系突变导致良性和恶性形式的肝癌而没有肝硬化。功能 G6 PC复发突变或G6 PC表达缺失与HCC发病机制的相关性尚不清楚。我 假设G6 PC缺失刺激肿瘤细胞生长所需的合成代谢途径, 足以驱动肝细胞增殖和肿瘤起始。本提案的具体目标是(1) 确定G6 PC的丢失如何改变代谢以支持肿瘤生长,(2)测试G6 PC是否可以增加 探讨G6 PC缺失对小鼠肝癌发生和发展的影响 HCC模型。我们将使用G6 PC缺陷的体外和体内模型,忠实地概括GSD 1a的各个方面, 稳定同位素示踪分析G6 PC的丢失如何重新连接代谢途径。 总之,这些目的将阐明G6 PC丢失如何影响HCC的非侵袭性发展, 深入了解糖原累积病1a型。我们希望能确定肝细胞癌的代谢负担 发病机制,可能提供新的治疗策略,这种致命的疾病。
英文摘要
PROJECT SUMMARY Although hepatocellular carcinoma (HCC) is the most common form of liver cancer, there are few therapies that are effective in treating this malignant disease. With less than 10% of patients who have HCC surviving beyond 5 years, it is important to identify additional therapeutic vulnerabilities. Metabolic alterations are a key feature of HCC pathogenesis, and represent targets that may reveal liabilities in HCC. Glucose-6-Phosphatase (G6PC) is recurrently downregulated in HCC and the magnitude of this downregulation correlates with patient outcome. Sequencing studies of HCCs reveal that somatic mutations occur in a subset of these malignancies. Additional evidence for G6PC involvement in HCC comes from Glycogen Storage Disease Type 1a (GSD1a), where germline mutations in G6PC lead to benign and malignant forms of liver cancer without cirrhosis. The functional relevance of recurrent mutations in G6PC or loss of G6PC expression to HCC pathogenesis in unclear. I hypothesize that loss of G6PC stimulates anabolic metabolic pathways required for tumor cell growth and are sufficient to drive hepatocyte proliferation and tumor initiation. The Specific Aims of this proposal aim to (1) determine how loss of G6PC alters metabolism to support tumor growth, (2) test whether G6PC can increase proliferation, and (3) explore ways in which G6PC loss influences liver tumors initiation and progression in mouse HCC models. We will use G6PC deficient in vitro and in vivo models that faithfully recapitulate aspects of GSD1a biology in patients, and stable isotope tracing to dissect how loss of G6PC rewires metabolic pathways. Altogether, these Aims will elucidate how G6PC loss influences non-cirrhotic development of HCC, and will provide insight into Glycogen Storage Disease Type 1a. We hope to identify metabolic liabilities in HCC pathogenesis that may provide new therapeutic strategies for this deadly disease.
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The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma
  • 批准号:
    10343735
  • 项目类别:
  • 资助金额:
    $3.88万
  • 财政年份:
    2021
  • 负责人:
    Sherwin Kelekar
  • 依托单位:
The Role of Glucose-6-Phosphatase in Hepatocellular Carcinoma
  • 批准号:
    10560507
  • 项目类别:
  • 资助金额:
    $4.74万
  • 财政年份:
    2021
  • 负责人:
    Sherwin Kelekar
  • 依托单位:
国内基金
海外基金
Cd(II)在NH2-Agar/PSS双网络水凝胶上的吸附行为及资源化工艺研究
  • 批准号:
    51708204
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    25.0万元
  • 批准年份:
    2017
  • 负责人:
    周贵寅
  • 依托单位: