Transforming Growth Factor - Beta Superfamily Signaling in Diabetes and Obesity

转化生长因子 - 糖尿病和肥胖症中的β超家族信号传导

• 批准号: 7734209
• 负责人: Sushil Rane
• 金额: $ 38.43万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734209
• 关键词: Action Research; Activins; Adult; Apoptosis; Beta Cell; Biology; Bone Morphogenetic Proteins; Cell Line; Cell Nucleus; Cell physiology; Cells; Cellular biology; Cessation of life; Complex; Development; Diabetes Mellitus; Disease; Dose; Ductal; Embryo; Endocrine; Endocrine Glands; Enzymes; Epithelial Cells; Epithelium; Exocrine pancreas; Family; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Glucose; Growth; Hormones; Inhibin-beta Subunits; Insulin; Islets of Langerhans; Lead; Ligand Binding; Malignant neoplasm of pancreas; Mediating; Mesenchyme; Morphogenesis; Obesity; Pancreas; Pancreatic Diseases; Pancreatitis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Protein Isoforms; Proteins; Receptor Activation; Receptor Serine/Threonine Kinase; Recruitment Activity; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Smad Proteins; Smad protein; TGF-beta type I receptor; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factor beta; cell growth; cell type; design; improved; insulin secretion; interest; islet; programs; receptor; response; transcription factor

Activated TGF-beta family factors signal via dual Type II (TbetaRII) and dual Type I (TbetaRI/Activin-like kinase 5/ALK5) transmembrane serine/threonine kinases receptors and effector Smad transcription factors. While TGF-beta signaling is critical during endocrine pancreas development, whether TGF-beta plays a role in maintaining adult beta-cell function is unclear. Interestingly, TGF-beta levels are elevated in diabetes, diabetes-associated complications, and obesity. Using primary islets and established beta-cell lines, we are examining the role of various TGF-beta isoforms and their respective receptors on the regulation of key pancreatic specific genes. Smad proteins are the established intracellular effectors of TGF-beta signaling and upon TGF-beta ligand binding, the activated TbetaRI/ALK-5 receptors recruit and phosphorylate receptor-Smads, i.e., Smad2 and Smad3. We are examining the roles of various Smad proteins, in the regulation of gene expression specific to the pancreas. TGF-beta signalling is known to suppress proliferation and promote growth arrest, differentiation/apoptosis of cells of the epithelial lineage. However, the role of this pathway in the growth, proliferation, differentiation and death of constituent pancreatic epithelial cells is unknowm. Using primary islets and established pancreatic ductal and beta cell lines, we are examining the role of TGF-beta signaling in these processes. Of particular interest will be the contribution of TGF-beta signaling in regulation of beta cell mass amd beta cell function. We are using primary islets, and established beta cell lines to examine the effects of TGF-beta isoforms, its receptor activation/inactivation, on beta cell mass and beta cell function. In addition the role of downstream Smad proteins is also being investigated. Several parallel approaches will be taken to explore this issue, which will hopefully lead to an improved understanding of the role of this complex signaling pathway in pancreatic development and specifically in regulation of beta cell mass and function. The information gained will be useful to delineate the role of this pathway in diseases of the pancreas.

活化的TGF-β家族因子通过双重II型（TbetaRII）和双重I型（TbetaRI/激活素样激酶5/ALK 5）跨膜丝氨酸/苏氨酸激酶受体和效应子Smad转录因子发出信号。虽然TGF-β信号在内分泌胰腺发育过程中至关重要，但TGF-β是否在维持成人β细胞功能中发挥作用尚不清楚。有趣的是，TGF-β水平在糖尿病、糖尿病相关并发症和肥胖症中升高。 使用原代胰岛和已建立的β细胞系，我们正在研究各种TGF-β亚型及其各自的受体对关键胰腺特异性基因调控的作用。Smad蛋白是TGF-β信号传导的既定细胞内效应物，并且在TGF-β配体结合后，激活的TbetaRI/ALK-5受体募集并磷酸化受体-Smad，即，Smad 2和Smad 3。我们正在研究各种Smad蛋白在胰腺特异性基因表达调控中的作用。 已知TGF-β信号传导抑制增殖并促进上皮谱系细胞的生长停滞、分化/凋亡。然而，该途径在组成胰腺上皮细胞的生长、增殖、分化和死亡中的作用尚不清楚。利用原代胰岛和已建立的胰腺导管和β细胞系，我们正在研究TGF-β信号在这些过程中的作用。 特别感兴趣的将是TGF-β信号传导在β细胞群和β细胞功能调节中的贡献。我们使用原代胰岛和已建立的β细胞系来研究TGF-β亚型、其受体活化/失活对β细胞质量和β细胞功能的影响。此外，下游Smad蛋白的作用也正在研究中。将采取几种平行的方法来探讨这个问题，这将有望导致更好地了解这个复杂的信号通路在胰腺发育中的作用，特别是在β细胞的质量和功能的调节。所获得的信息将是有用的，以描绘这一途径的胰腺疾病中的作用。