Mechanisms of IGF-1 mediated rescue of radiation-induced salivary gland dysfuncti

描述（由申请人提供）：头颈部癌症的放射治疗在正常唾液腺中引起明显的继发副作用，导致这些患者的生活质量下降。典型的放射敏感组织具有高增殖率和低分化水平。然而，唾液腺具有相反的特征，低水平增殖和高水平分化，表明它们对辐射不敏感。初步结果表明，放射暴露后早期诱导的细胞凋亡病理与唾液腺功能减退有关。表达组成型激活Akt （myr-Akt1）的转基因小鼠在接受治疗剂量的电离辐射后可恢复唾液流率。作为翻译这些研究的一种手段，我们之前已经证明，与其他生长因子相比，胰岛素样生长因子（IGF1）在唾液腺泡细胞中诱导了强劲的Akt激活（59）。放疗前静脉注射重组IGF1可完全恢复治疗后30天的唾液流量。本提案的总体目标是通过研究放射治疗后的细胞周期阻滞和增殖来确定IGF1保存唾液腺功能的机制。我们假设唾液腺对辐射的敏感可能是由于p53介导的凋亡病理立即激活而没有细胞周期阻滞。适当激活和释放细胞周期检查点可能是改善唾液腺功能的一种机制。特异性目的1将评估IGF1预防辐射诱导小鼠唾液腺凋亡病理的能力。特异性目标2将研究放射治疗后细胞周期阻滞激活。特异性Aim 3将确定延迟IGF1给药恢复辐射诱导的唾液腺功能障碍小鼠增殖和功能的能力。这些研究的一个独特和创新的优势是利用IGF1对抗辐射诱导的唾液腺功能障碍的翻译前景，以及表达构成型活性Akt突变体的转基因小鼠来破译IGF1的潜在机制。本研究的长期目标是评估在头颈部照射前对唾液腺进行IGF1治疗是否可以改善唾液腺功能障碍和口干症的临床治疗。这些研究将大大提高我们对应激环境下唾液腺生物学的理解，并且为患者的唾液腺导管插管的独特能力为临床应用提供了乐观的前景。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.