HB-EGF as a central regulator of pancreatic beta-cell proliferation

HB-EGF 作为胰腺 β 细胞增殖的中心调节因子

• 批准号: 9381112
• 负责人: VINCENT POITOUT
• 金额: $ 22.17万
• 依托单位: UNIVERSITY OF MONTREAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381112
• 关键词: Acids; Adolescent; Adult; Agonist; B Cell Proliferation; B-Lymphocytes; Beta Cell; Body mass index; Cell Proliferation; Cell physiology; Collaborations; Data; Development; Diabetes Mellitus; EGF gene; Epidermal Growth Factor Receptor; FOXM1 gene; FRAP1 gene; Fatty acid glycerol esters; Financial compensation; Funding; G-Protein-Coupled Receptors; Genetic; Glucose; High Fat Diet; Hour; Human; Immunodeficient Mouse; Immunology; Individual; Infusion procedures; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Knock-out; Malignant Neoplasms; Mediating; Membrane; Metabolic stress; Metalloproteases; Mitogens; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Pharmacology; Physiological; Pregnancy; Receptor Activation; Receptor Signaling; Regulation; Reporting; Research Institute; Risk; Rodent; Role; Signal Transduction; Somatostatin; Structure of beta Cell of islet; Testing; Therapeutic; Transplantation; Universities; Wistar Rats; autocrine; design; exenatide; feeding; gene induction; heparin-binding EGF-like growth factor; in vivo; insight; islet; novel strategies; paracrine; prevent; response; type I and type II diabetes

One in ten adults will have diabetes by 2040. Both type 1 (T1D) and type 2 diabetes (T2D) are characterized by a reduction in functional β-cell mass. Our overarching hypothesis is that a precise understanding of the molecular mechanisms controlling human β-cell proliferation may provide novel strategies to 1.) expand functional β-cell mass prior to islet transplantation in T1D; and 2.) prevent or delay the development of T2D in individuals at risk. The specific objective of this project is to elucidate the role of heparin-binding EGF-like growth factor (HB-EGF) in the control of β-cell proliferation. Previous findings and recent data from our group provide a strong basis for this proposal and include: 1.) HB-EGF is a potent human β-cell mitogen; 2.) HB-EGF expression in human islets correlates with Body Mass Index; 3.) β-cell proliferation in response to glucose and other β-cell mitogens is blocked by inhibition of HB-EGF or EGF receptor (EGFR) signaling; 4.) somatostatin (SST) blocks HB-EGF-induced β-cell proliferation. These data led us to formulate the hypothesis that autocrine/paracrine HB-EGF signaling through EGFR in β-cells integrates positive and negative signals to regulate β-cell proliferation. This hypothesis will be tested by: 1.) Investigating whether glucose and other mitogens promote β-cell proliferation via HB-EGF-dependent EGFR activation in isolated rodent and human islets. Then the mechanism involved in metalloproteinase-dependent shedding of HB-EGF from its membrane-bound precursor will be determined using genetic and pharmacological approaches. 2.) Elucidating the mechanisms by which SST and other inhibitory G protein-coupled receptors (GPCR) dampen glucose-induced EGFR signaling in isolated rodent and human islets. In particular, whether this is mediated by direct interaction between inhibitory GPCRs and the EGFR will be investigated in collaboration with M. Bouvier at the Institut de Recherche en Immunologie et Cancérologie. 3.) Ascertaining the role of HB-EGF in β-cell compensation using a conditional β-cell specific knockout approach in mice in response to high-fat feeding and gestation. The importance of HB-EGF for human β-cell proliferation will be confirmed by transplanting HB-EGF-deficient juvenile human islets into exendin-4-treated immunodeficient mice, a model established by our collaborator A. Powers at Vanderbilt University. Dissecting the mode of regulation and mechanism of action of HB-EGF will provide important insights into the regulation of β-cell proliferation. From a therapeutic perspective, these findings may help design novel strategies to expand β-cell mass prior to islet transplantation in T1D and to maintain or expand functional β-cell mass in T2D.

到2040年，十分之一的成年人将患有糖尿病。1型（T1D）和2型糖尿病（T2D）的特征都是功能性β细胞质量减少。我们的首要假设是，对控制人类β细胞增殖的分子机制的精确理解可能为以下方面提供新的策略：1.)在T1D患者胰岛移植前扩大功能性β细胞质量；2)预防或延缓高危人群发生T2D。本项目的具体目的是阐明肝素结合egf样生长因子（HB-EGF）在控制β-细胞增殖中的作用。我们小组以前的发现和最近的数据为这一建议提供了强有力的基础，包括：HB-EGF是一种有效的人β细胞有丝分裂原；2)。人胰岛HB-EGF表达与体重指数的相关性研究3)。抑制HB-EGF或EGF受体（EGFR）信号传导可阻断β细胞对葡萄糖和其他β细胞有丝分裂原的增殖；4)生长抑素（SST）阻断hb - egf诱导的β-细胞增殖。这些数据使我们提出假设，自分泌/旁分泌HB-EGF信号通过β细胞中的EGFR整合正、负信号来调节β细胞增殖。这一假设将通过以下方式进行验证：研究葡萄糖和其他有丝分裂原是否通过hb - egf依赖性EGFR激活促进β细胞增殖。然后，利用遗传和药理学方法确定金属蛋白酶依赖性HB-EGF从其膜结合前体脱落的机制。2)。阐明SST和其他抑制G蛋白偶联受体（GPCR）抑制离体鼠和人胰岛中葡萄糖诱导的EGFR信号的机制。特别是，这是否由抑制性gpcr和EGFR之间的直接相互作用介导，将与免疫学和癌症研究所的M. Bouvier合作进行研究。3)。利用条件β细胞特异性敲除方法确定HB-EGF在小鼠对高脂肪喂养和妊娠的β细胞补偿中的作用。HB-EGF对人β细胞增殖的重要性将通过将HB-EGF缺陷的幼年人胰岛移植到exendin-4处理的免疫缺陷小鼠（我们的合作者a . Powers在Vanderbilt大学建立的模型）中得到证实。剖析HB-EGF的调控模式和作用机制，将对β-细胞增殖的调控提供重要的见解。从治疗的角度来看，这些发现可能有助于设计新的策略，在T1D胰岛移植前扩大β细胞团，并在T2D中维持或扩大功能性β细胞团。