Radiation therapy for head and neck cancer causes significant secondary side effects in the normal salivary gland resulting in diminished quality of life for these patients. Classically radio- sensitive tissues have high rates of proliferation coupled with a low level of differentiation. However, salivary glands convey the opposite characteristics with a low level of proliferation and high level of differentiation suggesting that they should not be sensitive to radiation. Preliminary results have indicated that apoptotic pathology induced early after radiation exposure correlates with salivary gland hypofunction. Transgenic mice expressing a constitutively activated Akt (myr-Akt1) rescues salivary flow rates following a therapeutic dose of ionizing radiation. As a means to translate these studies, we have previously shown that insulin-like growth factor (IGF1) induces robust Akt activation in salivary acinar cells when compared to other growth factors (59). Intravenous injections of recombinant IGF1 prior to radiation exposure completely rescues salivary flow rates 30 days after treatment. The general goal of this proposal is to identify the mechanisms of IGF1 preservation of salivary gland function by investigating cell cycle arrest and proliferation following radiation therapy. We hypothesize that the exquisite sensitivity of the salivary glands to radiation may be due to immediate activation of p53-mediated apoptotic pathology without cell cycle arrest. Appropriate activation and release of cell cycle checkpoints may be one mechanism to improve salivary gland function.
Specific Aim 1 will evaluate the ability of IGF1 to prevent radiation-induced apoptotic pathology in the salivary glands of mice.
Specific Aim 2 will investigate cell cycle arrest activation following treatment with radiation.
Specific Aim 3 will determine the ability of delayed IGF1 administration to restore proliferation and function in mice with radiation-induced salivary gland dysfunction. A unique and innovative strength of these studies is the translational promise of using IGF1 to counter radiation-induced salivary gland dysfunction and transgenic mice that express a constitutively active mutant of Akt to decipher potential mechanisms of IGF1. The long-term goal of this proposal is to evaluate whether IGF1 treatment of salivary glands prior to head and neck irradiation could improve clinical therapeutics for salivary gland dysfunction and xerostomia. These studies will significantly improve our understanding of salivary gland biology in stressed environments and the unique ability to cannulate salivary gland ducts in patients provides optimism for clinical application.
Radiation is a common treatment in most head and neck cancer cases and results in the loss of saliva in most patients. The resulting lack of salivary gland activity results in significant adverse side effects, which diminish the effectiveness of anti-cancer therapies, and decreases the quality of life for these patients. The general goal of this proposal is to identify mechanisms to preserve salivary gland function following exposure to radiation by evaluating cellular repair mechanisms and cell growth. The studies could have the potential to prevent or restore salivary gland function to head and neck cancer patients.
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|Chibly, Alejandro M; Querin, Lauren; Harris, Zoey et al. (2014) Label-retaining cells in the adult murine salivary glands possess characteristics of adult progenitor cells. PLoS One 9:e107893|
|Morgan-Bathke, Maria; Hill, Grace A; Harris, Zoey I et al. (2014) Autophagy correlates with maintenance of salivary gland function following radiation. Sci Rep 4:5206|
|Morgan-Bathke, Maria; Harris, Zoey I; Arnett, Deborah G et al. (2014) The Rapalogue, CCI-779, improves salivary gland function following radiation. PLoS One 9:e113183|
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|Morgan-Bathke, M; Lin, H H; Chibly, A M et al. (2013) Deletion of ATG5 shows a role of autophagy in salivary homeostatic control. J Dent Res 92:911-7|
|Martin, Katie L; Hill, Grace A; Klein, Rob R et al. (2012) Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model. PLoS One 7:e51363|
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|Grundmann, Oliver; Fillinger, Jamia L; Victory, Kerton R et al. (2010) Restoration of radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF-1 administration. BMC Cancer 10:417|
|Mitchell, Gc; Fillinger, Jl; Sittadjody, S et al. (2010) IGF1 activates cell cycle arrest following irradiation by reducing binding of Ã½Ã½Np63 to the p21 promoter. Cell Death Dis 2010:e50|
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