Olfactory Stem and Progenitor Cell Plasticity

Tufts University Boston, Boston MA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): The goal of this NRSA F31 award is to provide support for my Ph.D. training at Tufts University, Sackler School. In this application, I have described a thorough outline of my training plan including research training, thesis work, and other activities, all designed to prepare me for a successful career in academic research. The olfactory epithelium (OE) is a pseudostratified epithelium containing olfactory sensory neurons (OSNs), glial-like sustentacular (Sus) cells, and basal stem cells. This tissue continually undergoes adult neurogenesis, replacing neurons lost due to environmental factors as well as natural turnover. Pathways which link the basal cells to the mature and differentiated cell types through unidirectional transcription factor cascades have been generated by observing OE development and repair. However, more recent observations during development provide evidence that these unidirectional cascades may not be the rule-indeed-there is a high degree of plasticity between the basal cell populations during development. These data, along with results obtained in the larger stem cell field have suggested that this may also be the case in the adult OE. I have begun preliminary investigations into the lineage commitments of the cell types that can be isolated using fluorescently tagged reporter mouse lines using transplantation assays. In this application, I describe that normal development follows the unidirectional cascades as expected. On the other hand, following damage, neuronally committed progenitors were able to generate glial-like Sus cells which are of a separate lineage. Accordingly, the proposed research for this F31 application investigates this previously unreported case of damage-induced plasticity by further characterizing this plasticity in-situ as well as studying potential mechanisms. Specific Aim 1 further characterizes the damage induced plasticity of the Neurog1+ cells in-situ compared to after transplant using genetic lineage tracing. In addition, transplantation time courses will show whether this plasticity goes through a defined intermediate or if this is a case of transdifferentiation. Specific Aim 2 explors the observation that these Neurog1+ cells up-regulate the pluripotency and stemness protein Sox2 after damage. I will use both genetic ablation as well as viral based expression to test if Sox2 is necessary and sufficient for this plasticity. The proposed research work combined with the wide breadth of career development opportunities described further in the application are all designed to provide the training and foundation necessary for a successful career in academic research.