Salivary gland repair and regeneration via Schwann cell-nerve interactions

描述（由申请人提供）：唾液腺功能障碍是头颈癌放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。唾液的功能和再生，以及 上皮祖细胞的维持依赖于副交感神经支配：只有在维持副交感神经输入的情况下才会发生再生。目前的努力，再生唾液组织和恢复功能没有解决需要修复副交感神经支配。因此，在本申请中，我们提出通过使用雪旺细胞重建神经供应来恢复唾液功能。雪旺细胞对于神经元功能、存活和再生以及维持组织神经支配是必不可少的。我们假设，在放射后维持雪旺细胞，或将自体雪旺细胞移植到放射损伤的唾液腺中，将增强神经元输入并促进组织再生。因此，本项目的具体目的是：1）确定伽马辐射对雪旺细胞-神经元细胞相互作用的影响; 2）确定神经产生的Neuregulin-1对辐射后雪旺细胞和神经元存活、神经功能和上皮再生的影响; 3）确定辐射后雪旺细胞恢复唾液功能的能力。这些目标将实现使用胚胎离体和成年小鼠在体内模型的照射下颌下腺结合遗传，生物化学，免疫化学和荧光成像技术。重要的是，将平行分析来自辐照人腺体的活检。我们的研究将提供足够的原理证明，以支持在人类研究中的再生策略的发展，并促进我们对辐射如何影响唾液腺再生和修复的理解。 头颈癌放射治疗后，唾液腺会受到不可逆的损伤，这会大大降低口腔健康和生活质量。该项目采用辐射诱导唾液腺损伤的胚胎和成年小鼠模型，开发一种使用神经支持细胞（称为Schwann细胞）的方法，以重新建立腺体修复、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再生治疗方法，用于恢复人类患者的唾液功能。

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.