Charlotte M. Mistretta - US grants

DESCRIPTION: (Adapted From the Applicants Abstract): This proposal deals with the role of several neurotrophic factors in the fetal development of sensory neurons that innervate taste buds, and interactions between fetal cell types in the morphogenesis of mature taste organs. The P.I. will be able to use an organ culture system developed in her laboratory as an essential resource for all these goals. Firstly, the role of neurotrophic factors in supporting the development of the neurons the innervate taste buds have a different neurotrophic dependence than neurons from other sensory ganglia. Such dependence will be measured in terms of morphometric studies on neurite outgrowth and in terms of the development of critical electrophysiological properties in the sensory neurons. Secondly, the organ culture system will allow detailed analyses of any potential induction roles that embryonic tongue epithelium and mesenchyme may play in the formation of gustatory papillae. Finally, the interactions of the growing neurites of sensory neurons with developing taste buds will be examined. The later two aims will be approached by establishing mixed cultures of epithelium and mesenchyme or papillae and ganglia of different ages and morphogenetic potential. These data will form a significant body of knowledge about the development of the peripheral gustator system.

health science research support; university;

polygraphy; biomedical equipment resource;

biomedical equipment resource; biomedical equipment purchase;

biomedical equipment purchase;

DESCRIPTION (provided by applicant): Taste is a vital sense that depends on taste bud receptor complexes in the gustatory epithelia to direct eating and food choices. Taste bud cells and supporting epithelia turn over, are renewed throughout life, and are susceptible to environmental and pharmacological agents. Taste organs therefore depend on tightly regulated proliferation and differentiation. The Hedgehog (HH) pathway regulates maintenance of adult stem and progenitor cells in many tissues. Our data implicate HH signaling as a principal regulator of maintenance and renewal of taste receptor organs. However, HH activity not only regulates tissue maintenance, but also uncontrolled HH signaling is the cause of basal cell carcinoma (BCC), a common skin tumor. Therefore, HH Pathway Inhibitors (HPIs) that block signaling by affecting the HH pathway effector, Smoothened, have been developed as targeted therapeutics for BCC. HPIs lead to regression of BCCs, but patients often discontinue treatment due to adverse effects including severe taste disturbances. Our preliminary data suggest that the taste alterations are an on-target effect reflecting a strict requirement for HH signaling in taste function. We hypothesize that HH signaling functions to control renewal of taste organs and that pharmacological disruption of this control is responsible for chemosensory disturbances in patients treated with HPIs. We use genetic models (mouse) and pharmacological treatment (mouse and human cancer patients) to study the taste system with altered HH signaling. Our Multi PI approach includes chemosensory and HH signaling biologists, and a clinician/scientist treating BCC patients with HPIs. In Aim 1 we hypothesize that HH signaling regulates taste bud and/or papilla maintenance and function through an essential role in epithelial tissue renewal. In mouse we analyze: Hh pathway gene expression pattern and signaling in taste organs throughout the oral cavity; taste bud receptor cell maintenance, renewal and function, during and after treatment with HPIs that target the signal transduction component Smoothened; and, in genetic models, effects of targeted deletion of Smoothened on taste organs. We study cell and tissue effects, and behavioral and neurophysiological taste function. In Aim 2 we propose that HH signaling acts to control taste organ maintenance and function in BCC patients, explaining why pharmacological inhibition of this pathway causes chemosensory disturbance. In patients receiving HPIs, we test predictions about the extent and time course of chemosensory disruption, before, during and after HPI treatment, with questionnaires and NIH Toolbox tests of taste and smell sensory function; and, we quantify the number and distribution of fungiform papillae to correlate with taste sensation tests. The project addresses mechanisms of HH signaling inhibition in altering taste organ dynamics and function. This knowledge contributes to explaining the poorly understood, taste disturbances in patients treated with HPIs, and could ultimately lead to dietary modifications or other approaches to ameliorate chemosensory disruption and improve quality of life.