NIH Director's Pioneer Award

最近的研究将注意力集中在有丝分裂生态位在调节干细胞中的作用上。 自我更新，并强调了蛋白多糖在形成这种微环境中的重要性。 然而，在基因密码被破译50多年后，我们不知道 蛋白多糖上的糖链是否编码了重要的生物学信息。潜力 如此复杂的Glyco代码？是巨大的，但人们对它的特征知之甚少 参与有丝分裂调节的蛋白多糖，或干细胞所需的信号机制 更新。 为了破译是否存在糖码，我们将识别指定干细胞的蛋白多糖 哺乳动物大脑的更新。我们将依靠一种基因方法来研究蛋白多糖生物学和 新开发的质谱学创新，可以对糖进行大规模分析 蛋白多糖的组成。我们将产生能够与同源基因结合的突变生长因子 受体，但不能结合蛋白多糖。我们将确定个别蛋白多糖 调节信号通路和由生长因子引起的生物反应，可能是通过 影响因子的位置、呈现或齐聚。我们将从关注以下内容开始 Sonic Hedgehog(Shh)是小脑、皮质和多种组织中干细胞的有丝分裂原。 癌症。我们将使用一种新的检测方法来鉴定Shh介导的增殖所需的蛋白多糖 有丝分裂的利基环境，我们将确定糖码如何调控干细胞的繁殖。AS 随着工作的进展，我们将扩大我们的研究范围，以定义调节蛋白多糖的结构 干细胞对EGF或成纤维细胞生长因子家族成员等其他因子的反应。这些研究将 有助于糖码的识别，并将确定维持茎的机制。 这样的研究可以导致对从阿尔茨海默氏病到 癌症到中风。

Recent studies have focused attention on the role of mitogenic niches in regulating stem cell self?renewal, and have emphasized the importance of proteoglycans in forming such microenvironments. However, more than 50 years after the genetic code was deciphered, we do not know whether sugar chains on proteoglycans encode biologically important information. The potential complexity of such a ?glyco code? is enormous, but little is known about the features of the proteoglycans involved in mitogenic regulation, or the signaling mechanisms required for stem cell renewal. To decipher whether there is a glyco code we will identify proteoglycans that specify stem cell renewal in the mammalian brain. We will rely on a genetic approach to proteoglycan biology and on newly developing innovations in mass spectrometry that allow large scale analysis of the sugar composition of proteoglycans. We will generate mutated growth factors capable of binding to cognate receptors, but unable to bind proteoglycans. We will ascertain whether individual proteoglycans modulate the signaling pathway and the biological response elicited by a growth factor, perhaps by influencing the location, presentation, or oligomerization of the factor. We will begin by focusing on Sonic Hedgehog (Shh), which is mitogenic for stem cells in the cerebellum, cortex, and in diverse cancers. We will identify proteoglycans required for Shh- mediated proliferation using a new assay for mitogenic niches, and we will determine how a glyco code might regulate stem cell propagation. As the work progresses we will extend our studies to define proteoglycan structures that modulate the response of stem cells to additional agents such as EGF or FGF family members. These studies will contribute to the identification of a glyco-code, and will determine mechanisms that maintain ?stemness?. Such studies can lead to enhanced therapies for disorders from Alzheimers disease to cancers to stroke.