Rescue of radiation-induced salivary gland dysfunction by Akt

描述（由申请方提供）：唾液腺是头颈部照射后异常细胞凋亡的部位，导致严重的腺体功能障碍。在治疗期间，这些患者暴露于多轮放射治疗，这对正常唾液腺造成了重大损失。转基因小鼠已经建立表达组成型激活的Akt 1（myr-Akt 1），显着降低了细胞凋亡的水平，在唾液腺暴露于有针对性的头部和颈部辐射。本提案中提出的初步结果表明，myr-Akt 1转基因小鼠在单次治疗剂量的电离辐射后也能挽救唾液流速，从而提供了细胞凋亡和唾液腺功能障碍之间的相关性。虽然这些结果是非常有希望的，但接受头颈癌治疗放射的患者接受多剂量放射治疗。这项建议的总体目标是确定Akt在分次剂量辐射后维持唾液腺功能和体内平衡的能力。作为转化这些研究的一种手段，我们之前已经表明，与其他生长因子相比，IGF 1在唾液腺泡细胞中诱导了强大的Akt激活（1）。该提案的长期目标是评估在头颈部照射之前对唾液腺进行IGF 1治疗是否可以原位激活Akt并影响唾液腺功能障碍和口干症的临床治疗。我们假设Akt通过增强DNA修复途径和抑制凋亡途径在治疗性放射后改善唾液功能中起关键作用。具体目标1将评价Akt在分次剂量的头颈部辐射后维持唾液腺功能的能力。具体目标2将研究Akt在调节DNA修复中的作用？放射性唾液腺功能障碍。这些研究的一个独特和创新的优势是使用表达Akt 1组成型活性突变体的转基因小鼠。该小鼠模型和这些小鼠的原代唾液腺泡细胞培养物允许在靶向头颈部动物照射中直接比较转基因小鼠与对照小鼠，并且能够将原代培养物的体外初步结果与组织学或生化变化的体内检查相关联。该提案还侧重于唾液腺功能障碍和治疗辐射敏感性的机制分析，以便将这些结果应用于翻译应用研究。这些研究将显著提高我们对应激环境中唾液腺生物学的理解，并且在患者中插管唾液腺导管的独特能力为临床应用提供了乐观。 放射治疗是大多数头颈癌病例的常见治疗方法，并导致大多数患者的唾液流失。由此导致的唾液腺活性的缺乏导致显著的副作用，这降低了抗癌疗法的有效性，并降低了这些患者的生活质量。该提案的总体目标是确定细胞死亡在暴露于辐射后唾液腺功能丧失中的作用，并评估是否可以在头部和颈部照射前使用防止细胞死亡的物质，以防止唾液腺功能障碍和口干症。

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.