Hepatocyte Growth Factor and The Pancreatic Beta Cell

肝细胞生长因子和胰腺β细胞

基本信息

批准号：
8472477
负责人：
Adolfo Garcia-Ocana
金额：
$ 33.6万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8472477
关键词：
Address Apoptosis Apoptotic Autoimmune Diabetes Award Beta Cell Body mass index Candidate Disease Gene Cell Death Cell Proliferation Cell Survival Cellular Stress Ceramides Cessation of life Chronic Cues Cytoprotection Data Development Diabetes Mellitus Diet Dose Environment Failure Fatty acid glycerol esters Functional disorder Funding Future Gene Targeting Genetic Transcription Glucose Glucose Intolerance Goals Growth Growth Factor Growth Factor Overexpression Hepatocyte Growth Factor Homeostasis Hormones Human Hypoxia In Vitro Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Knock-in Mouse Knockout Mice Lead Link Mediating Mitochondria Mitogens Modeling Mouse Models of Human Cancer Consortium Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutrient Obesity Pancreas Pancreatectomy Pathway interactions Phenotype Physiological Predisposition Pregnancy Protein p53 Publishing Replacement Therapy Research Research Project Grants Resistance Rodent Role Signal Pathway Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Skeletal Muscle Streptozocin Structure of beta Cell of islet TP53 gene Therapeutic Transactivation Transgenic Mice Transplantation Up-Regulation Variant base beta cell replacement cell growth cell type cytokine cytotoxicity deprivation diabetic patient fatty acid oxidation feeding gain of function glucose metabolism glucose transport improved in vivo inhibitor/antagonist insulin secretion interest islet loss of function meetings overexpression pifithrin pleiotropism programs public health relevance response trait treatment strategy

项目摘要

DESCRIPTION (provided by applicant): We have previously shown that hepatocyte growth factor (HGF) has beneficial effects in beta cell proliferation, function and islet transplantation. More recently, we have deciphered a dual role of HGF in beta cell survival. On one hand, HGF protects beta cells in situations of hypoxia, nutrient deprivation, streptozotocin-mediated cytotoxicity and cytokine-induced cell death. On the other hand, HGF potentiates beta cell death induced by gluco-lipoxicity in vitro. Metabolically, HGF decreases fatty acid oxidation and enhances ceramide content in beta cells. In terms of signaling, HGF-mediated activation of the beta cell pro-survival signal Akt is abolished in the presence of a gluco-lipotoxic insult. Circulating HGF levels are markedly high in obesity. Taken together, these results indicate that HGF might participate in beta cell failure in obesity/Type 2 diabetes in vivo. To address this question, in Specific Aim 1 we will characterize the functional consequences of disrupting HGF/c-met signaling in the pancreatic beta cell in vivo in obese/Type 2 diabetes conditions. Alterations in functional p53 levels often lead to increased apoptosis in many cell types. However, whether p53 has any regulatory role in directly controlling pancreatic beta cell death in obesity/Type 2 diabetes is unknown. Preliminary data from our lab clearly indicate that (i) gluco-lipotoxicity upregulates p53 expression and activation in beta cells; (ii) inhibition of p53 transactivation with the specific p53 inhibitor pifithrin-1 blocks gluco- lipotoxicity-mediated beta cell apoptosis; (iii) p53-null mouse beta cells are more resistant than wild-type beta cells to gluco-lipotoxicity-induced apoptosis; and, (iv) transgenic mice overexpressing p53 in the beta cell display glucose intolerance. Importantly, a recent comprehensive association study of obesity/type 2 diabetes and related quantitative traits has identified a single nucleotide polymorphism variant (Arg72Pro) in the TP53 gene in obese/Type 2 diabetic patients. Arg72-p53 variant has a higher apoptotic potential possibly through increased localization in the mitochondria. Taken together, these studies clearly highlight the potential link between alterations in p53 expression/activation/localization and pancreatic beta cell apoptosis, impaired insulin secretion, gluco-lipotoxicity and obesity/Type 2 diabetes. To address this point, in Specific Aim 2, we will decipher the functional consequences of gain-of-function, loss-of-function and the 72Arg variant of p53 in the beta cell in vivo under basal and obesity conditions. In Specific Aim 3, we will analyze the relevance of p53 in mediating human beta cell apoptosis and the mechanisms involved in p53-induced beta cell apoptosis in a gluco-lipotoxic environment in vitro. The proposed studies in rodent and human beta cells in vitro and in mice in vivo will provide valuable information to identify pathways to protect beta cells against dysfunction and death in situations of obesity- mediated Type 2 diabetes.

描述（由申请人提供）：我们先前表明，肝细胞生长因子（HGF）对β细胞增殖，功能和胰岛移植具有有益作用。最近，我们破译了HGF在β细胞存活中的双重作用。一方面，HGF在缺氧，营养剥夺，链蛋白酶介导的细胞毒性和细胞因子诱导的细胞死亡的情况下保护β细胞。另一方面，HGF会在体外增强葡萄糖脂毒性诱导的β细胞死亡。代谢，HGF降低脂肪酸氧化并增强β细胞中的神经酰胺含量。在信号传导方面，HGF介导的β细胞促生存信号AKT的激活在存在葡萄糖 - 糖毒性损伤的情况下被取消。循环的HGF水平明显高。综上所述，这些结果表明HGF可能会在体内参与肥胖症/2型糖尿病的β细胞衰竭。为了解决这个问题，在特定的目标1中，我们将表征破坏肥胖/2型糖尿病状况中胰腺β细胞中HGF/C-MET信号传导的功能后果。功能性p53水平的改变通常会导致许多细胞类型的凋亡增加。但是，p53在肥胖/2型糖尿病中直接控制胰腺β细胞死亡方面是否具有任何调节作用。来自我们实验室的初步数据清楚地表明，（i）葡萄糖 - 糖毒性上调了β细胞中的p53表达和激活；（ii）用特定的p53抑制剂pifithrin-1抑制p53抑制p53抑制作用，阻断葡萄糖脂肪毒性介导的β细胞细胞凋亡；（iii）p53-null小鼠β细胞比野生型β细胞更具耐药性，对葡萄糖脂毒性诱导的细胞凋亡；以及（iv）在β细胞显示葡萄糖不耐症中过表达p53的转基因小鼠。重要的是，肥胖/2型糖尿病和相关定量性状的近期综合关联研究确定了肥胖/2型糖尿病患者的TP53基因中的单个核苷酸多态性变体（ARG72PRO）。 ARG72-P53变体具有较高的凋亡潜力，这可能是通过线粒体中的定位增加的。综上所述，这些研究清楚地表明了p53表达/激活/定位的改变与胰腺β细胞细胞凋亡，胰岛素分泌受损，葡萄糖糖毒性和肥胖/2型糖尿病之间的潜在联系。为了解决这一点，在特定的目标2中，我们将在基础和肥胖条件下的beta细胞中beta细胞中p53的功能损益，功能丧失和72arg变体的功能后果。在特定的目标3中，我们将分析p53在介导人β细胞凋亡中的相关性以及在体外葡萄糖 - 糖毒性环境中p53诱导的β细胞凋亡中涉及的机制。在体外和体内小鼠中对啮齿动物和人β细胞的拟议研究将提供有价值的信息，以确定在肥胖介导的2型糖尿病的情况下保护β细胞免受功能障碍和死亡的途径。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of HGF/c-Met signaling in pancreatic β-cells leads to incomplete maternal β-cell adaptation and gestational diabetes mellitus.

DOI：
10.2337/db11-1154
发表时间：
2012-05
期刊：
Diabetes
影响因子：
7.7
作者：
Demirci C;Ernst S;Alvarez-Perez JC;Rosa T;Valle S;Shridhar V;Casinelli GP;Alonso LC;Vasavada RC;García-Ocana A
通讯作者：
García-Ocana A

Hepatocyte growth factor/c-Met signaling is required for β-cell regeneration.

DOI：
10.2337/db13-0333
发表时间：
2014-01
期刊：
Diabetes
影响因子：
7.7
作者：
Alvarez-Perez JC;Ernst S;Demirci C;Casinelli GP;Mellado-Gil JM;Rausell-Palamos F;Vasavada RC;Garcia-Ocaña A
通讯作者：
Garcia-Ocaña A

Mechanisms in the adaptation of maternal β-cells during pregnancy.

DOI：
10.2217/dmt.10.24
发表时间：
2011-03-01
期刊：
Diabetes management (London, England)
影响因子：
0
作者：
Ernst S;Demirci C;Valle S;Velazquez-Garcia S;Garcia-Ocaña A
通讯作者：
Garcia-Ocaña A

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.

DOI：
10.2337/db09-1305
发表时间：
2011-02
期刊：
Diabetes
影响因子：
7.7
作者：
Mellado-Gil J;Rosa TC;Demirci C;Gonzalez-Pertusa JA;Velazquez-Garcia S;Ernst S;Valle S;Vasavada RC;Stewart AF;Alonso LC;Garcia-Ocaña A
通讯作者：
Garcia-Ocaña A

Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes.