Transforming Growth Factor - Beta Superfamily Signaling in Diabetes and Obesity

激活的转化生长因子-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/Alk5)跨膜丝氨酸/苏氨酸激酶受体和效应转录因子Smad来传递信号。尽管转化生长因子-β信号在胰腺内分泌发育过程中起关键作用，但转化生长因子-β是否在维持成人β细胞功能方面发挥作用尚不清楚。有趣的是，转化生长因子-β水平在糖尿病、糖尿病相关并发症和肥胖症中升高。 利用原代胰岛和已建立的β细胞系，我们正在研究各种转化生长因子-β亚型及其各自的受体在关键胰腺特异性基因调控中的作用。Smad蛋白是转化生长因子-β信号转导的细胞内效应分子，与转化生长因子-β配体结合后，激活的TbetaRI/ALK-5受体募集并磷酸化Smads受体，即Smad2和Smad3。我们正在研究各种Smad蛋白在胰腺特异基因表达调控中的作用。 已知转化生长因子-β信号通路可抑制上皮细胞的增殖，促进上皮细胞的生长停滞、分化/凋亡。然而，该通路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管和β细胞系，我们正在研究转化生长因子-β信号在这些过程中的作用。 特别令人感兴趣的是转化生长因子-β信号在调节β细胞质量和β细胞功能中的作用。我们使用原代胰岛，并建立了β细胞系，以检测转化生长因子-β亚型及其受体激活/失活对β细胞质量和β细胞功能的影响。此外，下游Smad蛋白的作用也在研究中。将采取几种平行的方法来探索这一问题，这将有望使人们更好地理解这一复杂的信号通路在胰腺发育中的作用，特别是在调节β细胞质量和功能方面。所获得的信息将有助于描述这一途径在胰腺疾病中的作用。

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.