The long-term objective of this project is to investigate intercellular signaling mechanisms that regulate progenitor cell proliferation and neurogenesis in the olfactory epithelium (OE). Short-term, using target ablation to induce neuronal apoptosis followed by a synchronous wave of macrophage activation/infiltration and progenitor cell proliferation, this project focuses on the role of macrophages as sources of bioactive molecules that regulate intercellular signaling. Innovative use of transgenic mice in pilot studies demonstrated that in the absence of activated macrophages, progenitor cell proliferation is substantially reduced following target ablation. The data implicate the chemokine macrophage inflammatory protein (MIP)-1alpha and its receptor CCR1 in macrophage recruitment and suggest that the class A macrophage scavenger receptor (MSR-A) is involved in the clearance of apoptotic neurons, thus linking apoptosis, phagocytosis, cell proliferation, and neurogenesis. The proposed in vivo experiments focus on cellular and molecular events that occur at 2 his to 72 hrs after target ablation, when macrophage infiltration and subsequent signaling is initiated, by addressing three specific aims. The first is to characterize the tune course of mRNA expression for MIP-1alpha and CCR1 following target ablation and to localize their proteins in the OE. The second is to assess the effects of the absence of MIP-1alpha protein in MIP-1alpha-/- mice on macrophage infiltration and progenitor cell proliferation and to determine if the effects can be modulated by exogenous MIP-1alpha protein in knockout mice. The third is to examine the expression of MSR-A as a mediator of phagocytic clearance of apoptotic neurons by macrophages by comparing clearance in wild-type mice and MRS-A-/ mice. Gene profiling methodology will be used in the experiments on knockout mice to examine the involvement of additional chemokine receptors and/or signaling cascades. These studies will elucidate key components of the signaling pathways leading to progenitor cell proliferation and neurogenesis in the OE and establish the use of two new animal models in which to investigate OE cell dynamics in vivo. Understanding the signaling regulating neurogenesis in the OE will yield insights into mechanisms for restoring olfactory function compromised by aging, trauma, and neurodegenerative diseases.
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