Senescence and Salivary Gland Dysfunction

摘要 正常的衰老过程、放射治疗(RT)的副作用以及以下症状都可能导致肺功能低下 自身免疫性疾病导致各种负面后遗症，包括龋齿、口臭和 消化功能减退。干燥综合征(SS)是一种影响唾液腺的自身免疫性外分泌疾病， 0.4%的美国人的泪腺和其他外分泌器官，大多数患者是40岁以上的女性(9：1 女性与男性的比例)。SS的主要缺陷是外分泌腺功能分泌上皮的丧失。 导致功能丧失的机制是复杂的和多因素的，但包括免疫依赖和 延伸到正常衰老和RT的免疫非依赖性病理。细胞衰老是一种重要的肿瘤- 阻止细胞增殖并对伤口愈合有积极影响的抑制机制，但当激活时 慢性，会加剧组织损伤和功能丧失。最近的研究表明，衰老的细胞在 SS患者的唾液腺，因为RT，在正常衰老期间。细胞衰老对唾液的影响 SS和其他情况下的功能减退尚不完全清楚。随着年龄增长而积累的衰老细胞采用 衰老相关分泌表型(SASP)，其特征是分泌细胞因子、生长因子和 破坏组织动态平衡并导致与年龄相关的病理变化的蛋白酶。SASP与组织有因果关系 通过旁分泌作用对邻近细胞的退化，以及对衰老细胞的遗传消融可以保护器官功能 通过限制SASP。类似地，系统地去除衰老细胞的抗衰老药物可以增加整体健康和寿命。 在老鼠身上。最小化SASP可限制炎症反应的幅度和持续时间，限制 外分泌功能，延缓与疾病相关的器官衰退。我们已经确定了几个控制SASP和SASP的microRNA 炎性细胞因子基因表达可作为限制衰老细胞活性的靶点。这些研究详细介绍了 这里将检验这样的假设：衰老促进SS样疾病中未消退的炎症驱动唾液腺 功能减退。我们将通过选择性地调节以有机类物质为基础的和 唾液腺功能低下的小鼠模型。我们建议处理以下具体目标：1.界定 衰老和Sjögren综合征相关miRNAs在SASP调控中的作用。目标2.确定是否 消融衰老细胞或靶向促进SASP的miRNAs可以减少未消退的炎症和 体内纤维化。3.明确衰老细胞SASP在SS疾病发展中的作用。这项研究将进一步 我们对衰老、炎症和唾液腺功能减退之间的联系的理解。比较研究 基因和RNA介导的衰老细胞消减方法和SASP表型调控的反配子将 揭示基于RNA的潜在治疗策略，用于SS患者和其他患者的唾液腺功能恢复 老化或受损的器官。

ABSTRACT Hyposalivation can result from the normal aging process, a side-effect of radiation therapy (RT), and a symptom of autoimmune disease leading to a variety of negative sequelae including increased incidence of dental caries, halitosis, and reduced digestive function. Sjögren’s Syndrome (SS) is an autoimmune exocrinopathy affecting the salivary glands, lacrimal glands, and other exocrine organs in 0.4% of the US population, with most patients being women over 40 (9:1 female to male ratio). The primary deficit underlying SS is the loss of functional secretory epithelium in exocrine glands. The mechanisms leading to loss of function are complex and multifactorial but include both immune-dependent and immune-independent pathologies that extend to normal aging and RT. Cellular senescence is an important tumor- constraining mechanism that halts cellular proliferation and has positive impacts on wound healing but, when activated chronically, can exacerbate tissue injury and loss of function. Recent work demonstrated that senescent cells accumulate in the salivary glands of SS patients, because of RT, and during normal aging. How cellular senescence contributes to salivary hypofunction in SS and other conditions is incompletely understood. Senescent cells that accumulate with age adopt a senescence-associated secretory phenotype (SASP) characterized by the secretion of cytokines, growth factors, and proteases that disrupt tissue homeostasis and contribute to age-related pathologies. SASP is causally linked to tissue degeneration by paracrine effects on neighboring cells, and genetic ablation of senescent cells can preserve organ function by limiting SASP. Similarly, senolytic drugs that systemically ablate senescent cells can increase general health and lifespan in mice. Minimization of SASP may limit the amplitude and duration of the inflammatory response, restrict the loss of exocrine function, and delay disease-related organ decline. We have identified several microRNAs that control SASP and inflammatory cytokine gene expression that can be used as targets to limit the activity of senescent cells. The studies detailed here will test the hypothesis that senescence promotes non-resolving inflammation in SS-like disease to drive salivary gland hypofunction. We will test our hypothesis by selective modulation of the senescence program in both organoid-based and murine models of salivary gland hypofunction. We propose to address the following specific aims: 1. Define the contribution of senescence- and Sjögren’s Syndrome-associated miRNAs in SASP regulation. Aim 2. Determine if ablation of senescent cells or targeting of miRNAs promoting SASP can reduce non-resolving inflammation and fibrosis in vivo. 3. Define the contribution of the senescent cell SASP to SS disease development. This study will further our understanding of the link between senescence, inflammation, and salivary gland hypofunction. Studies comparing genetic and RNA-mediated methods for senescent cell abatement and antagomiRs for SASP phenotype modulation will reveal potential RNA-based therapeutic strategies for the functional restoration of salivary glands of SS patients and other aged or injured organs.