Impact of aging on salivary stem cells and organ regeneration

 描述(申请人提供)：唾液腺功能障碍是头颈癌放射治疗后的病理损伤以及自身免疫性疾病Sjögren综合征的结果，严重影响患者的口腔健康和生活质量。恢复唾液功能的一种潜在的再生方法是sem细胞疗法，即将自体干细胞/祖细胞移植到受损的器官中，或者组织内的干细胞重新激活。然而，尽管绝大多数45岁或45岁以上的唾液功能障碍患者以及众所周知的随着年龄增加而出现的唾液腺结构和功能的不利变化，但在唾液腺动态平衡和再生过程中，衰老对干细胞行为的影响尚不清楚。在这项应用中，我们建议确定衰老对唾液腺前体细胞的稳态和再生功能的影响，以及副交感神经系统对它们的调节。副交感神经对唾液功能和再生以及上皮祖细胞的维持都是必不可少的，但对衰老对这些器官功能神经的影响知之甚少。鉴于衰老通常与腺泡萎缩和周围神经功能减退有关，我们假设衰老破坏了维持组织内环境平衡和介导损伤后器官再生所需的胆碱能干细胞通讯。在这个提案中，我们将通过两个具体的目标来解决我们的中心假设：1)确定衰老对SOX2+前体细胞的稳态和再生能力的影响以及副交感神经对它们的调节；2)确定SOX2+前体细胞在衰老过程中的分子和表型变化。这些目标将利用人类唾液腺和小鼠的遗传学以及遗传、生化、免疫化学和高分辨率成像技术相结合来实现。我们研究这一假说的基本原理是，了解衰老对干细胞/祖细胞的自我稳定和再生能力的影响，以及对调节其行为的过程的影响，对于它们在逆转唾液功能障碍方面的治疗应用至关重要。

 DESCRIPTION (provided by applicant): Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer as well as due to the autoimmune disease Sjögren's Syndrome and significantly compromises the oral health and quality of life of patients. A potential regenerative approach for restoring salivary function is sem cell therapy, where autologous stem/progenitor cells are transplanted into the injured organ or stem cells within the tissue are reactivated. However, despite the vast majority of patients with salivary dysfunction aged 45yrs or older and the well described adverse alterations in salivary gland structure and function that occurs with increasing age, the effects of aging on stem cell behavior during salivary gland homeostasis and regeneration are not known. In this application we propose to determine the impact of aging on the homeostatic and regenerative function of salivary progenitor cells and their regulation by the parasympathetic nervous system. Parasympathetic nerves are essential to salivary function and regeneration, as well as for the maintenance of epithelial progenitor cells, but very little is known regarding the influence of aging on the functional innervation of these organs. Given that aging is often associated with acinar atrophy and reduced peripheral nerve function, we hypothesize that aging disrupts cholinergic-stem cell communication required to maintain tissue homeostasis and mediate organ regeneration after injury. In this proposal we will address our central hypothesis via two specific aims: 1) Define the effect of aging on the homeostatic and regenerative capacity of SOX2+ progenitor cells and their regulation by parasympathetic nerves and 2) Identify molecular and phenotypic alterations in SOX2+ progenitor cells during aging. These aims will be achieved using a combination of human salivary glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and high resolution imaging techniques. Our rationale for investigating this hypothesis is that understanding the effects of aging on the homeostastic and regenerative capacity of stem/progenitor cells and on processes that regulate their behavior is vital to their therapeutic application in reversing salivary dysfunction.