NIH Director's Pioneer Award

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications & trials

Abstract

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