We have demonstrated previously that Clara cell (CC) progenitors that express Uroplakin3a (Upk3a) are clustered around Neuroepithelial Bodies (NEBs) from early stages in lung development. In this proposal we focus on Upk3a-expressing Clara cells (U-CCs) in the adult mouse lung. U-CCs are enriched around NEBs, seem to survive Naphthalene (Nap) injury and proliferate afterwards. U-CCs are more abundant in Nap treated lungs one month after injury. Our central hypothesis is that U-CC expansion post injury depends on NEBs that maintain U- CCs, and on the Notch signaling pathway that regulates the proliferation of U-CCs. We will test this hypothesis by pursuing the following Specific Aims.
In Aim1 we will determine whether NEBs are required to maintain U-CCs prior to and post injury. We hypothesize that the ablation of NEBs will prevent the expansion of U-CCs post injury.
In Aim2 we will examine the role of Notch1 in the proliferation of U-CCs post injury. We hypothesize that in the absence of Notch1 the progeny of U-CCs will acquire a post-mitotic ciliated fate and that the expansion of U-CCs will not occur.
In Aim 3 we will determine whether U-CCs can self-renew during homeostasis and define the lineage-generating potential of this cell type. Individual differences in the response to an environmental toxin may be the outcome of differences in the frequencies of airway-resident cell populations. In this proposal we investigate how the injury-repair process impacts the frequency of a specific airway cell type.
The incidence of environmentally-induced lung disorders is increasing worldwide. While it is known that prolonged exposure to pollutants, dust and other environmental toxins, affect some individuals more than other, the underlying reasons are obscure. Differences in the responses to these toxins may be important in this regard. Respiratory tract repair is dependent on progenitor or stem cells. Here we describe an injury-resistant population of airway progenitors that increase in abundance after injury and propose to investigate how the expansion of this population is regulated. The expansion of such injury-resistant populations may vary among individuals and lead to distinct outcomes upon subsequent challenge.