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

• 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
• 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

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）：头颈癌的放射治疗会对正常唾液腺造成显着的继发副作用，导致这些患者的生活质量下降。传统的放射敏感组织具有高增殖率和低分化水平。然而，唾液腺却表现出相反的特征，即低水平的增殖和高水平的分化，表明它们对辐射不敏感。初步结果表明，辐射暴露后早期诱导的细胞凋亡病理与唾液腺功能减退相关。表达组成型激活的 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速。作为转化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) 可诱导唾液腺泡细胞中的强劲 Akt 激活 (59)。在辐射暴露前静脉注射重组 IGF1 可完全恢复治疗后 30 天的唾液流量。该提案的总体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 保存唾液腺功能的机制。我们推测唾液腺对辐射的高度敏感性可能是由于 p53 介导的细胞凋亡病理学立即激活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改善唾液腺功能的机制之一。具体目标 1 将评估 IGF1 预防小鼠唾液腺中辐射诱导的细胞凋亡病理的能力。具体目标 2 将研究放射治疗后细胞周期停滞的激活。具体目标 3 将确定延迟 IGF1 给药恢复辐射引起唾液腺功能障碍的小鼠增殖和功能的能力。这些研究的独特和创新优势是利用 IGF1 对抗辐射引起的唾液腺功能障碍的转化前景，以及表达 Akt 组成型活性突变体的转基因小鼠来破译 IGF1 的潜在机制。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 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。这些研究将显着提高我们对应激环境下唾液腺生物学的理解，并且在患者体内插管唾液腺管的独特能力为临床应用提供了乐观的前景。 公共卫生相关性：放射是大多数头颈癌病例的常见治疗方法，会导致大多数患者唾液流失。由此导致的唾液腺活性缺乏会导致显着的副作用，从而降低抗癌治疗的有效性，并降低这些患者的生活质量。该提案的总体目标是通过评估细胞修复机制和细胞生长来确定暴露于辐射后保存唾液腺功能的机制。这些研究有可能预防或恢复头颈癌患者的唾液腺功能。