Rescue of radiation-induced salivary gland dysfunction by Akt

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DESCRIPTION (provided by applicant): Salivary glands are the site of aberrant apoptosis following head and neck irradiation resulting in severe glandular dysfunction. During therapy, these patients are exposed to multiple rounds of radiation treatment which takes a significant toll on the normal salivary gland. Transgenic mice have been created expressing a constitutively activated Akt1 (myr-Akt1) which significantly reduces the level of apoptosis in the salivary glands following exposure to targeted head and neck radiation. Preliminary results presented in this proposal have indicated the myr-Akt1 transgenic mice also rescue salivary flow rates following a single therapeutic dose of ionizing radiation providing a correlation between apoptosis and salivary gland dysfunction. While these results are very promising, patients undergoing therapeutic radiation for head and neck cancer receive multiple doses of radiation. The general goal of this proposal is to define the ability of Akt to maintain salivary gland function and homeostasis following fractionated doses of radiation. As a means to translate these studies, we have previously shown that IGF1 induces robust Akt activation in salivary acinar cells when compared to other growth factors (1). The long-term goal of this proposal is to evaluate whether IGF1 treatment of salivary glands prior to head and neck irradiation could activate Akt in situ and impact clinical therapeutics for salivary gland dysfunction and xeriostomia. We hypothesize that Akt plays a pivotal role in improved salivary function following therapeutic radiation by enhancement of DNA repair pathways and suppression of apoptotic pathways. Specific Aim 1 will evaluate the ability of Akt to maintain salivary gland function following fractionated doses of head and neck radiation. Specific Aim 2 will investigate the role of Akt in regulating DNA repair in ?-irradiation-induced salivary gland dysfunction. A unique and innovative strength of these studies is the use of transgenic mice that express a constitutively active mutant of Akt1. This mouse model and primary salivary acinar cell cultures from these mice allow the direct comparison of transgenic mice with control mice in targeted head and neck animal irradiation and the ability to relate in vitro preliminary results from primary cultures with in vivo examination of histological or biochemical changes. This proposal also focuses on a mechanistic analysis of salivary gland dysfunction and sensitivity to therapeutic radiation in order to apply these results towards translation application studies. 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 the 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 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 define the role cell death serves in loss of salivary gland function following exposure to radiation and evaluate whether substances that prevent cell death could be used prior to head and neck irradiation in order to prevent salivary gland dysfunction and xerostomia.