Mouse Models of Accelerated Aging of the Olfactory System: Targeting the Stem Cell Compartment
Child, Kevin.
2019
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Aging is a
degenerative disease that leads to a decline in physiologic function. The olfactory
epithelium (OE) is a highly regenerative neuroepithelium that is visibly and
quantifiably affected by aging. In previous studies, we have seen an increase in the
incidence of olfactory dysfunction in the human population with age. At the cellular
level, histological assessment of the olfactory area ... read moreof patients with age-related
olfactory disorders have revealed patches of aneuronal OE, i.e., regions that lack
neurons as well as a loss of Globose Basal Cells (GBCs), the proliferative stem cell of
the OE responsible for epithelial reconstitution. In this thesis I replicate in mice
what is seen in human OE by forcing the GBCs to accelerate proliferation with the goal
of exhausting their proliferative potential. I use two different approaches to force
this exhaustion 1) the continuous turnover of mature olfactory neurons through a genetic
cell ablation model using DTA expression and 2) a targeted approach which kills off the
proliferating GBCs through administration of a chemotherapeutic agent that targets
dividing cells or through Gamma-irradiation. These manipulations result in an OE that
closely resembles aged human OE. The enhanced depletion of olfactory neurons leads to an
expansion of the GBCs to compensate for neuronal loss and patchy emergence of aneuronal
OE, which lacks both neurons and GBCs but remains olfactory. In addition, some of the
areas that were previously olfactory undergo respiratory metaplasia, which is also
observed in aged human OE. In these models, degeneration of the tissue is not limited to
the OE but also affects the olfactory bulb. The OB appears to shrink in size as the
number of neurons decreases across the OE in association with a reduction in the axonal
innervation and in the number of neuronal synapses from the nose to the OB. This thesis
also investigates another population of stem cell in the OE that is quiescent, the
Horizontal Basal Cell (HBC), which appears to be unaffected by the depletion of the
GBCs. This thesis provides new tools for the field of aging and olfactory research and
suggests a method by which olfaction might be restored in patients with various
age-related olfactory dysfunction/decline.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Genetics.
Advisor: James Schwob.
Committee: Pamela Yelick, Philip Hinds, Peter Juo, and Richard Costanzo.
Keyword: Genetics.read less - ID:
- rv0436233
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