The goal of this NRSA F31 award is to provide support for my Ph.D. training. A thorough outline of my research training, coursework, and research thesis are described in the application, all of which are designed to prepare for a successful career in academic science. The proposed research investigates the spatial regulation of olfactory receptor (OR) expression and neuronal identity during olfactory neurogenesis. ORs are expressed in stripes along the olfactory epithelium (OE), a characteristic that is essential for proper development of the olfactory circuit, yet, it remains unknown when and how spatially influenced gene choices occur during olfactory neurogenesis. Each olfactory sensory neuron (OSN) expresses one OR out of over 1000 different OR genes. OR gene selection defines the functional neuronal `cell fate' of each OSN. Additionally, dorsal OSNs express the enzyme NQO1, while ventral OSNs express the olfactory cell adhesion molecule, OCAM, providing another measure of spatial gene expression across the OE. Understanding how and when spatially influenced neuronal cell fate commitment occurs is essential to answering outstanding questions in olfactory biology and is critical for informing the potential development of olfactory transplantation therapies for people with reduced sense of smell, or anosmia (a condition that affects 1/2 of those 65-80, degrading nutrition and quality of life). During transplantation, it is crucial that transplanted cells are committed to a neuronal lineage, but malleable in respect to spatially influenced cell fates in order to avoid negative systems such as phantosmia, characterized by olfactory hallucinations. The stem (SC) and progenitor cell populations of OE can be broken down into different stages of neuronal commitment from SCs with the ability to give rise to all OE cell types, to immediate neuronal precursors (INPs), one stage prior to the immature neurons. OR/NQO1/OCAM expression begins in the immature neurons and it is likely that spatial gene choice immediately precedes expression; thus, Specific Aim 1 tests whether the NQO1 vs. OCAM gene choice has occurred by the INP stage of olfactory neurogenesis, through a series of transplantation experiments.
Specific Aim 2 tests the hypothesis that OR gene choice is influenced by spatial cues, through a series of transplantation, single-cell RT-PCR and in situ hybridization experiments. The proposed research work will be coupled with rich career development opportunities including meeting attendance, grant writing, manuscript writing, and teaching opportunities. Thus, the described research is designed to provide the foundation for a successful career in academic science.
Decreased olfactory function, termed anosmia, affects 1/2 of those 65-80, degrading nutritional status and quality of life. This proposal aims to understand when and how spatial cues influence neuronal cell fate decisions in the olfactory epithelium, with the ultimate goal of informing the development of safe transplantation therapies for the over 200,000 people each year seeking anosmia treatment.
|Coleman, Julie H; Lin, Brian; Schwob, James E (2017) Dissecting LSD1-Dependent Neuronal Maturation in the Olfactory Epithelium. J Comp Neurol 525:3391-3413|
|Lin, Brian; Coleman, Julie H; Peterson, Jesse N et al. (2017) Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency. Cell Stem Cell 21:761-774.e5|
|Schwob, James E; Jang, Woochan; Holbrook, Eric H et al. (2017) Stem and progenitor cells of the mammalian olfactory epithelium: Taking poietic license. J Comp Neurol 525:1034-1054|
|Schnittke, Nikolai; Herrick, Daniel B; Lin, Brian et al. (2015) Transcription factor p63 controls the reserve status but not the stemness of horizontal basal cells in the olfactory epithelium. Proc Natl Acad Sci U S A 112:E5068-77|