Mechanisms of Hedgehog Mediated Rescue of Radiation-induced Hyposalivation

刺猬介导的辐射引起的唾液分泌不足的救援机制

• 批准号: 8508916
• 负责人: Fei Liu
• 金额: $ 34.99万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508916
• 关键词: Acinar Cell; Adult; Adverse effects; Agonist; Animal Model; Artificial Saliva; Cancer Survivor; Cells; Cues; DTR gene; Data; Deterioration; Development; Duct (organ) structure; Erinaceidae; Evolution; Family suidae; Female; Gender; Gene Delivery; Goals; Head and Neck Cancer; Human; Impairment; In Vitro; Injury; Integrins; Lead; Ligation; Maintenance; Mediating; Molecular; Mus; Natural regeneration; Neonatal Brain Injury; Pathway interactions; Patients; Population; Production; Quality of life; Radiation; Radiation therapy; Saliva; Salivary; Salivary Glands; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Stem cells; Symptoms; Syndrome; Testing; Tissues; Up-Regulation; Xerostomia; base; functional loss; functional restoration; head and neck cancer patient; human SMO protein; in vivo; irradiation; male; mouse model; notch protein; prevent; progenitor; public health relevance; receptor; regenerative therapy; repaired; research study; response; restoration; saliva secretion; self-renewal; small molecule; species difference; stem; success; tissue regeneration

DESCRIPTION (provided by applicant): This application is in response to RFA-DE-12-004, Functional Restoration of Salivary Glands (R01). Hypofunction of salivary gland is a common pathological condition in patients with Sjogren's syndrome or treated with radiotherapy for head and neck cancer. Current treatments can only temporarily relieve the symptoms, while regenerative therapies based on adult salivary gland stem cells have shown potential to restore salivary gland function in animal models but limited by technical hurdles and lack of understanding of molecular mechanisms. Hedgehog intercellular pathway is highly conserved during evolution and regulates regeneration or repair of various tissues after injury. We found previously that Hedgehog activity is marginal in adult salivary gland but significantly upregulated during their functional regeneration after physical injury; our preliminary data suggested that in salivary glands of both male and female mice, radiation impairs maintenance and differentiation of salivary stem/progenitor cells, and does not activate Hedgehog pathway, while transient Hedgehog activation after radiation in male mice significantly rescued salivary flow rates, possibly by both maintenance of salivary stem/progenitor cells and their differentiation after radiation. The goal of this project is understanding the mechanisms of Hedgehog-mediated rescue of hyposalivation, which will lead to optimization of this approach or development of more efficient and safer approaches to restore salivary function. To achieve this goal, we will: (1) determine the effects and mechanisms of transient Hedgehog activation on maintenance of salivary stem/progenitor cells after radiation; (2) determine the effects and mechanisms of transient Hedgehog activation on differentiation of salivary stem/progenitor cels after radiation; and (3) determine the effects of gender- or species-differences on Hedgehog mediated resuce of radiation-induced hyposalivation. Success of proposed experiments will open a new avenue for functional restoration of salivary glands after radiotherapy.

描述（由申请人提供）：此申请响应RFA-DE-12-004，唾液腺功能恢复（R01）。唾液腺功能障碍是Sjogren综合征患者或接受放射疗法治疗头颈癌的常见病理状况。当前的治疗只能暂时缓解症状，而基于成人唾液腺干细胞的再生疗法显示出可能在动物模型中恢复唾液腺功能的潜力，但受到技术障碍和对分子机制的了解的限制。刺猬在进化过程中高度保守细胞间途径，并调节损伤后各种组织的再生或修复。我们以前发现，刺猬活性在成人唾液腺中很小，但显着上调 在身体受伤后的功能再生期间；我们的初步数据表明，在雄性和雌性小鼠的唾液腺中，辐射会损害唾液干/祖细胞的维持和分化，并且未激活刺猬途径，而在男性小鼠中辐射后辐射后的瞬时刺猬激活，可以通过两种唾液流动率显着拯救唾液流动率，这可能是通过两种维持的唾液茎/偏源剂的辐射及其不同的辐射，其不同的辐射效果均不同。该项目的目的是了解刺猬介导的挽救性能的机制，这将导致优化这种方法或开发更有效，更安全的方法以恢复唾液功能。为了实现这一目标，我们将：（1）确定瞬时刺猬激活对辐射后唾液干/祖细胞维持的影响和机制； （2）确定瞬时刺猬激活对辐射后唾液茎/祖细胞分化的影响和机制； （3）确定性别或物种差异对刺猬介导的辐射诱导的低余化活化的影响。拟议的实验的成功将为放射疗法后的唾液腺功能恢复开辟新的途径。