Wnt signaling and hematopoietic stem cells

Children'S Hospital & Res Ctr At Oakland, Oakland CA

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Abstract

DESCRIPTION (provided by applicant): Stem cells hold great therapeutic promise for a variety of diseases. These cells are unique in that they are capable of self-renewal or differentiation into various tissue cell types. Factors that regulate the ultimate fate of stem cells include members of the Wnt protein family. Wnt proteins function by binding to cell surface receptors of the frizzled and low-density lipoprotein receptor-related protein families. Following binding, a signal is transduced to ss-catenin, which then enters the nucleus and forms a complex with T cell factor / lymphoid enhancer factor, activating transcription of Wnt target genes. The goal of proposed research is to generate a soluble, active Wnt protein for use in studies of signaling and stem cell self-renewal. In Aim 1 it is hypothesized that nanoscale bilayer disk particles, termed nanodisks (ND), will provide a lipid surface for Wnt fatty acyl chain insertion, thereby anchoring Wnt to the particle in a biologically active conformation. In Aim 2 it is hypothesized that Wnt3a-ND will possess biological activity in signal transduction and colony forming cell assays using hematopoietic stem cells. The hypothesis that inclusion of apolipoprotein E as ND scaffold protein will affect Wnt3a-ND activity through binding to the Wnt co-receptor LRP5 will be tested. The effect of including all trans retinoic acid as a component of Wnt3a-ND will be evaluated to determine if additive or synergistic stem cell self renewal activity will be observed. Execution of these studies will provide new results on a potential aqueous soluble Wnt3a binding complex that preserves the potent biological activity of members of this protein family. Defining conditions to induce expansion of HSC will have profound effects on disease treatment options and outcomes. PUBLIC HEALTH RELEVANCE: Stem cells hold exceptional promise as therapy for disease. A critical aspect related to the application of stem cells for therapy is an ability to regulate their fate, in terms of differentiation versus proliferation. An important signal transduction pathway involved in stem cell regulation is mediated by the "Wnt" protein. Studies to be undertaken will establish an optimized Wnt signaling system and evaluate stem cell responsiveness as a function Wnt association with specialized nanoparticles.