Smad Regulation of Pancreatic Islet Formation

描述（由申请人提供）：TGF-β超家族信号传导长期以来与胰腺内分泌细胞发育，特别是胰腺β细胞形成密切相关。由于超家族的规模和复杂性，很难清楚地了解信号传导机制。转录因子的smad家族是一个相对较小的家族，其充当TGF-β超家族信号传导的下游介体。由于其相对简单，我们选择专注于smad信号转导，以便开始解开TGF-β超家族分子调节胰岛细胞形成，特别是β细胞的关键机制。我们有初步的证据表明，TGF-β超家族信号，通过smads 2和3，控制招聘的内分泌祖细胞从胚胎小鼠的多能胰腺上皮细胞。在最初募集内分泌祖细胞后，这些smads似乎随后调节胰腺内分泌成熟和增殖。这两个smads的功能似乎是关键调制的抑制smads之一，smad 7。重要的是，我们也发现了smads 2和3，以及抑制性smad 7在成年小鼠胰腺部分切除后新β细胞再生中的潜在平行作用。似乎大多数新的β细胞是从以前的β细胞形成的，但对调节这种新的β细胞形成的内源性细胞外信号知之甚少或一无所知。因此，该提案将集中于胚胎和再生胰岛中的smad信号传导，以便更好地理解通过TGF-β超家族导致新β细胞形成的细胞外信号传导。导致新的胰腺β细胞形成的细胞外信号传导机制的研究是重要的，因为用于治疗糖尿病的细胞工程应该仅涉及细胞外操作而不是细胞内（遗传）操作。我们已经确定了胚胎胰岛细胞形成和成人胰岛再生之间的关键平行关系，这可能使我们深入了解细胞外信号可用于工程β细胞的机制。公共卫生相关性：导致新的胰腺β细胞形成的细胞外信号传导机制的研究是重要的，因为用于治疗糖尿病的细胞工程应该仅涉及细胞外操作而不是细胞内（遗传）操作。我们已经确定了胚胎胰岛细胞形成和成人胰岛再生之间的关键平行关系，这可能使我们深入了解细胞外信号可用于工程β细胞的机制。

DESCRIPTION (provided by applicant): TGF-beta superfamily signaling has long been strongly implicated in pancreatic endocrine cell development and specifically pancreatic beta cell formation. Because of the size and complexity of the superfamily it has been difficult to garner a clear understanding of signaling mechanisms. The smad family of transcription factors is a relatively small family that serves as the downstream mediator of TGF-beta superfamily signaling. Because of its relative simplicity, we have chosen to focus on smad signaling in order to begin to unravel the key mechanisms by which TGF-beta superfamily molecules regulate pancreatic islet cell formation, especially beta cells. We have preliminary evidence that TGF-beta superfamily signaling, through smads 2 and 3, control recruitment of endocrine progenitor cells from the multipotent pancreatic epithelium in the embryonic mouse. After this initial recruitment of endocrine progenitor cells, these smads seem to then regulate pancreatic endocrine maturation and proliferation. The function of these two smads appears to be critically modulated by one of the inhibitory smads, smad7. Importantly, we have also shown a potential parallel role for smads 2 and 3, and the inhibitory smad7, in the regeneration of new beta cells in the adult mouse pancreas in response to a partial pancreatectomy. It appears that most new beta cells form from previous beta cells, but little or nothing is know about endogenous extracellular signals that regulate this new formation of beta cells. Thus, this proposal will focus on smad signaling in the embryo and in the regenerating islet in order to better understand the extracellular signaling through TGF-beta superfamily that leads to the formation of new beta cells. The study of extracellular signaling mechanisms that lead to new pancreatic beta cell formation are important since engineering of cells for the treatment of diabetes mellitus ought to involve only extracellular manipulations rather than intracellular (genetic) manipulations. We have identified a key parallel between embryonic islet cell formation and adult islet regeneration that may give us insights into the mechanisms by which extracellular signaling may be used to engineer beta cells. PUBLIC HEALTH RELEVANCE: The study of extracellular signaling mechanisms that lead to new pancreatic beta cell formation are important since engineering of cells for the treatment of diabetes mellitus ought to involve only extracellular manipulations rather than intracellular (genetic) manipulations. We have identified a key parallel between embryonic islet cell formation and adult islet regeneration that may give us insights into the mechanisms by which extracellular signaling may be used to engineer beta cells.