Smad Regulation of Pancreatic Islet Formation

描述（由申请人提供）：tgf - β超家族信号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。由于超家族的大小和复杂性，对信号机制的清晰理解一直很困难。smad转录因子家族是一个相对较小的家族，作为tgf - β超家族信号传导的下游介质。由于其相对简单，我们选择专注于smad信号，以便开始揭示tgf - β超家族分子调节胰岛细胞形成，特别是β细胞形成的关键机制。我们有初步证据表明，tgf - β超家族信号通过smads 2和3，控制胚胎小鼠多能性胰腺上皮内分泌祖细胞的募集。在初始募集内分泌祖细胞后，这些smad似乎调节胰腺内分泌的成熟和增殖。这两种smad的功能似乎受到其中一种抑制性smad smad7的严格调节。重要的是，我们还证明了smad2和3以及抑制性smad7在成年小鼠胰腺部分切除术后新β细胞再生中的潜在平行作用。似乎大多数新的β细胞是由先前的β细胞形成的，但对调节β细胞新形成的内源性细胞外信号知之甚少或一无所知。因此，本研究将重点关注胚胎和再生胰岛中的smad信号，以便更好地了解通过tgf - β超家族导致新β细胞形成的细胞外信号。研究导致新胰腺细胞形成的细胞外信号机制是很重要的，因为用于治疗糖尿病的细胞工程应该只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相似之处，这可能使我们深入了解细胞外信号传导可能用于改造β细胞的机制。公共卫生相关性：研究导致新胰腺β细胞形成的细胞外信号机制是重要的，因为用于治疗糖尿病的细胞工程应该只涉及细胞外操作，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相似之处，这可能使我们深入了解细胞外信号传导可能用于改造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.