Salivary gland repair and regeneration via Schwann cell-nerve interactions

描述(申请人提供)：唾液腺功能障碍是头颈癌放射治疗后病理损伤的结果，严重影响患者的口腔健康和生活质量。唾液功能和再生，以及 上皮祖细胞的维持依赖于副交感神经的支配：只有在维持副交感神经输入的情况下，才会发生再生。目前再生唾液组织和恢复功能的努力并没有解决修复副交感神经支配的需要。因此，在这一应用中，我们建议通过使用雪旺细胞重建神经供应来恢复唾液功能。雪旺细胞对神经元的功能、存活和再生以及维持组织神经支配都是必不可少的。我们假设，在辐射后维持雪旺细胞，或者将自体雪旺细胞移植到受辐射损伤的唾液腺中，将增加神经元的输入，促进组织再生。因此，该项目的具体目标是：1)确定伽玛辐射对雪旺细胞-神经细胞相互作用的影响；2)确定神经产生的NeuRegin-1对雪旺细胞和照射后神经元存活、神经功能和上皮再生的影响；以及3)确定雪旺细胞在辐射后恢复唾液功能的能力。这些目标将通过结合遗传、生化、免疫化学和荧光成像技术的颌下腺照射的胚胎体外和成年小鼠体内模型来实现。重要的是，来自受辐射的人类腺体的活组织检查将被平行分析。我们的研究将提供足够的原则证据，支持在人类研究中发展这一再生策略，并有助于我们理解辐射如何影响唾液腺的再生和修复。 与公共健康相关的头颈癌放射治疗后，唾液腺受到不可逆转的损害，这大大降低了口腔健康和生活质量。该项目利用胚胎和成年小鼠的辐射诱导唾液腺损伤模型，开发了一种使用神经支持细胞(称为雪旺细胞)的方法，以重建腺体修复、再生和分泌所必需的功能性神经供应。我们的目标是将这种方法发展成一种恢复人类患者唾液功能的再生疗法。

DESCRIPTION (provided by applicant): Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer and significantly compromises the oral health and quality of life of patients. Salivary function and regeneration, as well as the maintenance of epithelial progenitor cells, is dependent on parasympathetic innervation: regeneration only occurs if parasympathetic input is maintained. Current efforts to regenerate salivary tissue and restore function do not address the need to repair parasympathetic innervation. Therefore, in this application we propose to restore salivary function by re-establishing the nerve supply through the use of Schwann cells. Schwann cells are essential for neuronal function, survival and regeneration, and maintaining tissue innervation. We hypothesize that maintaining Schwann cells after radiation, or transplanting autologous Schwann cells into radiation-damaged salivary glands, will enhance neuronal input and promote tissue regeneration. Thus, the Specific Aims of this project are to: 1) Determine the impact of gamma radiation on Schwann cell-neuronal cell interactions; 2) Identify the effects of Neuregulin-1 produced by the nerves on Schwann cell and neuronal survival, nerve function, and epithelial regeneration after irradiation; and 3) Determine the ability of Schwann cells to restore salivary function after irradiation. These aims will be achieved using embryonic ex vivo and adult mouse in vivo models of irradiation in the submandibular gland in conjunction with genetic, biochemical, immunochemical, and fluorescence imaging techniques. Importantly, biopsies from irradiated human glands will be analyzed in parallel. Our investigation will provide sufficient proof-of-principle to support the development of this regenerative strategy in human studies and facillitate our understanding of how radiation influences salivary gland regeneration and repair. PUBLIC HEALTH RELEVANCE Salivary glands are irreversibly damaged after treatment with radiotherapy for head and neck cancer, and this substantially reduces oral health and quality of life. This project employs embryonic and adult mouse models of radiation-induced salivary gland injury to develop a method using the nerve support cells, called Schwann cells, to re-establish a functional nerve supply essential for gland repair, regeneration and secretion. Our goal is to develop this approach into a regenerative treatment for the restoration of salivary function in human patients.