NIH Director's Pioneer Award

最近的研究集中在有丝分裂小生境在调节干细胞中的作用 自我？更新，并强调了蛋白聚糖在形成这种微环境中的重要性。 然而，在遗传密码被破译50多年后，我们不知道 蛋白聚糖上的糖链是否编码生物学上重要的信息。的潜在 这样的复杂性？糖码？是巨大的，但很少有人知道的特点， 参与有丝分裂调节的蛋白聚糖，或干细胞所需的信号传导机制， 退款 为了破译是否存在糖密码，我们将鉴定指定干细胞的蛋白聚糖， 哺乳动物大脑的更新。我们将依赖于蛋白聚糖生物学的遗传学方法， 新开发的质谱创新，允许大规模分析糖 蛋白聚糖的组成。我们将产生突变的生长因子， 受体，但不能结合蛋白聚糖。我们将确定单个蛋白聚糖 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、呈现或寡聚化。我们将开始关注 Sonic Hedgehog（Shh），对小脑、皮质和多种组织中的干细胞具有促有丝分裂作用。 癌的我们将使用一种新的测定方法鉴定Shh介导的增殖所需的蛋白聚糖， 有丝分裂的壁龛，我们将确定如何糖代码可能调节干细胞繁殖。作为 随着工作的进展，我们将扩大我们的研究，以确定蛋白聚糖的结构，调节 干细胞对其他试剂如EGF或FGF家族成员的反应。这些研究将 有助于确定一个糖代码，并将确定机制，保持？sterness？ 这些研究可以导致从阿尔茨海默病到阿尔茨海默病的疾病的增强疗法， 从癌症到中风

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.