Impact of aging on salivary stem cells and organ regeneration

 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，也是自身免疫性疾病舍格伦综合征的结果，严重损害了患者的口腔健康和生活质量。一种潜在的恢复唾液腺功能的再生方法是sem细胞疗法，将自体干/祖细胞移植到受损器官中，或重新激活组织内的干细胞。然而，尽管绝大多数患有唾液腺功能障碍的患者年龄在45岁或以上，并且随着年龄的增加而发生唾液腺结构和功能的不良改变，但衰老对唾液腺稳态和再生期间干细胞行为的影响尚不清楚。在本申请中，我们提出确定衰老对唾液祖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。副交感神经是必不可少的唾液腺功能和再生，以及维持上皮祖细胞，但很少有人知道关于这些器官的功能神经支配的衰老的影响。鉴于衰老通常与腺泡萎缩和外周神经功能降低有关，我们假设衰老破坏了维持组织稳态和介导损伤后器官再生所需的胆碱能干细胞通讯。在该提案中，我们将通过两个具体目标来解决我们的中心假设：1）定义衰老对SOX 2+祖细胞的稳态和再生能力的影响以及副交感神经对其的调节，以及2）鉴定衰老期间SOX 2+祖细胞中的分子和表型改变。这些目标将通过结合人类唾液腺和小鼠遗传学以及遗传、生物化学、免疫化学和高分辨率成像技术来实现。我们研究这一假说的基本原理是，了解衰老对干/祖细胞的稳态和再生能力以及调节其行为的过程的影响，对于逆转唾液功能障碍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.