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

IGF-1介导的拯救辐射引起的唾液腺功能障碍的机制

• 批准号: 7900030
• 负责人: KIRSTEN H LIMESAND
• 金额: $ 33.32万
• 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/7900030
• 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（由申请方提供）：头颈癌的放射治疗在正常唾液腺中引起显著的继发性副作用，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，增殖水平低，分化水平高，这表明它们对辐射不敏感。初步研究结果表明，放射暴露后早期诱导的凋亡病理与唾液腺功能减退有关。转基因小鼠表达的组成型激活Akt（myr-Akt 1）救援唾液流量后，治疗剂量的电离辐射。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，胰岛素样生长因子（IGF 1）在唾液腺泡细胞中诱导了强烈的Akt激活（59）。放射暴露前静脉注射重组IGF 1可完全挽救治疗后30天的唾液流速。这项建议的总体目标是通过研究放射治疗后细胞周期阻滞和增殖来确定IGF 1保护唾液腺功能的机制。我们推测唾液腺对放射线的敏感性可能是由于p53介导的凋亡病理学的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IGF 1预防小鼠唾液腺中辐射诱导的凋亡病理的能力。具体目标2将研究放射治疗后的细胞周期阻滞激活。具体目标3将确定延迟IGF 1给药恢复放射诱导的唾液腺功能障碍小鼠的增殖和功能的能力。这些研究的一个独特和创新的优势是使用IGF 1来对抗辐射诱导的唾液腺功能障碍和表达Akt的组成型活性突变体的转基因小鼠的翻译承诺，以破译IGF 1的潜在机制。这项建议的长期目标是评估在头颈部照射之前对唾液腺进行IGF 1治疗是否可以改善唾液腺功能障碍和口干症的临床治疗。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。 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，并导致大多数患者唾液流失。由此导致的唾液腺活性的缺乏导致显著的不良副作用，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。本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护唾液腺功能的机制。这些研究有可能预防或恢复头颈癌患者的唾液腺功能。