Taste is a fundamental sense and is crucial for human health. Like our other primary senses, we consider our ability to appreciate sweet, sour, salty, bitter and umami tastes to be relatively constant, even though the taste bud cells that transduce these stimuli are renewed rapidly and regularly. The importance of the sense of taste is particularly evident for cancer patients receiving a range of chemotherapies, as these individuals often experience significant taste loss (ageusia) or dysfunction (dysgeusia). For patients with perturbed taste, simply eating a meal can be unpleasant or impossible; patients have significantly reduced quality of life including depression, lack of appetite and failure to maintain body weight, as well as poorer outcomes with cancer treatment. In particular, Basal Cell Carcinoma patients treated with drugs that target the Hedgehog (Hh) signaling pathway frequently experience dysgeusia. Interestingly Hh antagonists cause taste bud loss in mice, suggesting that functional taste loss in patients given these drugs is due to an effect on taste buds. Yet a mechanistic understanding of how taste bud homeostasis is impacted by Hh inhibition remains unexplored. And hence treatments to mitigate taste loss for cancer patients are yet to be imagined. Sonic hedgehog (Shh), one of 3 secreted Hh ligands, is implicated in taste bud cell renewal based on its expression pattern and that of its target gene, Gli1. A subset of taste bud cells is Shh+, while Gli1 expression is restricted to proliferating progenitor cells outside of buds, suggesting that Shh from within buds signals to adjacent progenitors to control taste cell turnover. However, the cellular and molecular processes regulated by Hh signaling are unknown, representing a significant gap in our knowledge of taste bud cell biology, and further limits our understanding of how Hh antagonists alter taste. Here, based on published reports and our pilot data, we propose the novel hypothesis that: Hedgehog signaling is required for taste receptor cell (TRC) differentiation and taste bud maintenance. We will test this overarching hypothesis using mouse models in 3 aims, and in completing these, greatly expand understanding of basic cellular and molecular mechanisms responsible for taste cell renewal, as well as define mechanistically how Hh pathway-targeted chemotherapy disrupts this process. Aim 1 Determine if Shh promotes TRC differentiation from taste progenitor cells. Aim 2 Identify the tissue source(s) of Shh required for TRC differentiation. Aim 3 Define cellular mechanisms underlying loss of differentiated TRCs in mice treated with Hh antagonist.

R01DC012383

2012-03-01

2022-02-28