This is a Shannon award providing partial support for the research projects that fall short of the assigned Institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. DESCRIPTION (Adapted from applicant's abstract): Dr. Niswander will test a model that proposes mutual interactions between the signals from the ridge, ZPA, and dorsal ectoderm, that serve to coordinate growth and pattern formation during limb development. She will focus on four outstanding questions related to embryonic limb development. How do these signals regulate each others activity? What genes are involved in establishing, and responding to, the ZPA and polarized ridge? How do cells interpret positional information? How does FGF signaling regulate biological responses in the limb? Specific Aim 1 is designed to address how Fgf4 is regulated by the endogenous ZPA. Further studies in this aim will identify genes that mediate establishment of the polarizing region and cell respecification. The studies in Specific Aim 2 will examine the regulation of Shh by FGF4 and the dorsal ectoderm and define the molecular nature of the dorsal ectoderm signal. Additional studies will explore how cells respond to SHH activity in defining their positional identity.
In Specific Aim 3, the mechanism of FGF4 action will be characterized by analysis of the FGF receptor signal transduction pathway. Signaling through the receptor will be disrupted using a panel of FGF receptor mutations. The biochemical, molecular and cellular processes that are regulated by FGF in the limb will be analyzed, both in vitro and in vivo, to determine whether specific developmental events are disrupted. Downstream components of the FGF signaling pathway will be used to rescue the mutant phenotype and substrate proteins that relay the FGF signal will be identified.
