Rescue of radiation-induced salivary gland dysfunction by Akt

描述（申请人提供）：唾液腺是头颈部照射后异常凋亡的部位，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，这对正常的唾液腺造成了重大损害。已经建立了表达组成型激活Akt1 （myr-Akt1）的转基因小鼠，该小鼠在暴露于靶向头颈部辐射后显著降低唾液腺的凋亡水平。本研究提出的初步结果表明，myr-Akt1转基因小鼠在单次治疗剂量的电离辐射后也能恢复唾液流速，这表明细胞凋亡和唾液腺功能障碍之间存在相关性。虽然这些结果非常有希望，但接受头颈癌治疗放疗的患者接受的是多剂量的放疗。本提案的总体目标是确定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，IGF1在唾液腺泡细胞中诱导了强劲的Akt激活(1)。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治疗是否能原位激活Akt，并影响唾液腺功能障碍和干口症的临床治疗。我们假设Akt通过增强DNA修复通路和抑制凋亡通路在放疗后唾液功能的改善中起关键作用。特异性目的1将评估Akt在分次头颈部放疗后维持唾液腺功能的能力。特异性目标2将研究Akt在调节DNA修复中的作用。-辐射引起的唾液腺功能障碍。这些研究的一个独特和创新的优势是使用表达Akt1组成活性突变的转基因小鼠。该小鼠模型和来自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下将转基因小鼠与对照小鼠进行直接比较，并能够将原代培养物的体外初步结果与体内组织学或生化变化检查联系起来。本研究还对唾液腺功能障碍和治疗放射敏感性进行了机制分析，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下唾液腺生物学的认识，并为患者唾液腺导管的独特插管能力提供了临床应用的乐观。

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.