Smad Regulation of Pancreatic Islet Formation

描述(申请人提供)：长期以来，转化生长因子-β超家族信号与胰腺内分泌细胞发育，特别是胰腺β细胞的形成密切相关。由于超家族的规模和复杂性，很难对信号机制有一个清楚的了解。Smad转录因子家族是一个相对较小的家族，是转化生长因子-β超家族信号的下游调节因子。由于其相对简单，我们选择将重点放在Smad信号上，以开始揭示转化生长因子-β超家族分子调控胰岛细胞形成的关键机制，特别是β细胞。我们已有初步证据表明，转化生长因子-β超家族信号通过Smads 2和3控制胚胎小鼠多潜能胰腺上皮中内分泌祖细胞的募集。在内分泌祖细胞的最初招募之后，这些Smad似乎随后调节胰腺内分泌成熟和增殖。这两个Smad的功能似乎受到抑制性Smad之一Smad7的关键调节。重要的是，我们还展示了Smads 2和3以及抑制Smad7在成年小鼠胰腺部分切除后新的β细胞再生中潜在的平行作用。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，本研究将重点关注胚胎和再生胰岛中的Smad信号，以更好地了解细胞外信号通过转化生长因子-β超家族导致新的β细胞的形成。研究导致新的胰岛β细胞形成的细胞外信号机制很重要，因为用于治疗糖尿病的细胞工程应该只涉及细胞外的操作，而不是细胞内的(遗传)操作。我们已经确定了胚胎胰岛细胞形成和成年胰岛再生之间的关键相似之处，这可能会让我们深入了解细胞外信号可能被用来设计β细胞的机制。公共卫生相关性：对导致新的胰岛β细胞形成的细胞外信号机制的研究很重要，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年胰岛再生之间的关键相似之处，这可能会让我们深入了解细胞外信号可能被用来设计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.