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

IGF-1介导的放射诱导唾液腺功能障碍的挽救机制

基本信息

批准号：
7879108
负责人：
KIRSTEN H LIMESAND
金额：
$ 0.59万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879108
关键词：
Adverse effects Aftercare Apoptotic Attenuated Biochemical Biological Preservation Biology Cancer Etiology Cell Cycle Arrest Cell Cycle Checkpoint Characteristics Clinical Coupled DNA Repair Dose Duct (organ) structure Effectiveness Environment Exposure to FVB Mouse Flow Cytometry Functional disorder Goals Growth Factor Head and Neck Cancer Head and neck structure IGF1 gene Injection of therapeutic agent Insulin-Like Growth Factor I Ionizing radiation Mediating Methods Mus Pathology Patients Phenotype Play Production Quality of life Radiation Radiation therapy Radio Recombinants Research Role Saliva Salivary Salivary Glands Signal Pathway Somatomedins Stress TP53 gene Therapeutic Tissues Transgenic Mice Transgenic Organisms Translating Xerostomia cancer therapy cell growth clinical application clinically relevant common treatment head and neck cancer patient improved in vivo innovation intravenous injection irradiation mutant optimism prevent public health relevance repaired response restoration salivary acinar cell senescence

项目摘要

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.

描述（由申请人提供）：头颈癌的放射治疗在正常唾液腺中引起显着的副作用，从而导致这些患者的生活质量降低。经典的放射性组织具有较高的增殖速率，并具有较低的分化水平。然而，唾液腺以低水平的增殖和高水平的分化传达相反的特征，这表明它们不应对辐射敏感。初步结果表明，凋亡病理在辐射暴露后早期诱导与唾液腺功能低下相关。表达组成型激活的Akt（MyR-AKT1）的转基因小鼠在治疗剂量的电离辐射剂量后挽救了唾液流速。作为翻译这些研究的一种手段，我们先前已经表明，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稳健的Akt激活（59）。在辐射暴露之前的重组IGF1的静脉注射完全挽救了治疗后30天的唾液流量。该提案的一般目标是通过研究放射治疗后的细胞周期停滞和增殖来确定IGF1保护唾液腺功能的机制。我们假设唾液腺对辐射的精致敏感性可能是由于立即激活p53介导的凋亡病理学而没有细胞周期停滞。细胞周期检查点的适当激活和释放可能是提高唾液腺功能的一种机制。具体目标1将评估IGF1预防小鼠唾液腺中辐射诱导的凋亡病理学的能力。特定的目标2将研究辐射治疗后的细胞周期停滞激活。具体的目标3将确定延迟IGF1给药恢复带有辐射诱导的唾液腺功能障碍的小鼠增殖和功能的能力。这些研究的独特而创新的强度是使用IGF1来抵抗辐射诱导的唾液腺功能障碍和转基因小鼠的转化诺言，这些小鼠表达了Akt的组成型活性突变体对IGF1的破译潜在机制。该提案的长期目标是评估在头部和颈部辐照之前对唾液腺的治疗是否可以改善唾液腺功能障碍和静脉疾病的临床治疗方法。这些研究将显着提高我们对压力环境中唾液腺生物学的理解，并在患者中插入唾液腺管道的独特能力为临床应用提供了乐观。公共卫生相关性：辐射是大多数头颈癌病例的常见治疗方法，导致大多数患者的唾液丧失。由于缺乏唾液腺活性导致严重的不良副作用，从而降低了抗癌疗法的有效性，并降低了这些患者的生活质量。该提案的一般目标是通过评估细胞修复机制和细胞生长来确定在暴露于辐射后保持唾液腺功能的机制。这些研究可能有可能预防或恢复头颈癌患者的唾液腺功能。