Senescence and Salivary Gland Dysfunction

衰老和唾液腺功能障碍

• 批准号: 10892708
• 负责人: MELINDA LARSEN
• 金额: $ 38.72万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10892708
• 关键词: 3-Dimensional; Abate; Ablation; Address; Adopted; Affect; Age; Autoimmune Diseases; Automobile Driving; Cell Aging; Cell Differentiation process; Cell Proliferation; Cell secretion; Cells; Chronic; Complex; Cytokine Gene; Dental caries; Deposition; Development; Disease; Drug Modelings; Duct (organ) structure; Epithelial Cells; Epithelium; Exocrine Glands; Experimental Models; Extracellular Matrix; Eye; Female; Fibrosis; Fluids and Secretions; Functional disorder; Ganciclovir; Gene Expression; Genetic; Gland; Growth Factor; Halitosis; Head and Neck Cancer; Health; Homeostasis; Human; Immune; Immune System Diseases; In Situ Hybridization; Inbred NOD Mice; Incidence; Inflammation; Inflammatory; Inflammatory Response; Iron; Label; Lacrimal gland structure; Ligation; Link; Longevity; Mediating; Methods; MicroRNAs; Modeling; Mus; Normal Cell; Operative Surgical Procedures; Oral cavity; Organ; Organ Preservation; Organoids; Pathology; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Population; Premature aging syndrome; Process; Production; Quality of life; RNA; RNA Sequences; Radiation therapy; Regulation; Reporting; Risk; Risk Factors; Saliva; Salivary; Salivary Glands; Severities; Signal Transduction; Sjogren' s Syndrome; Symptoms; Testing; Tissues; Untranslated RNA; Woman; Work; Xerostomia; age related; aged; autoimmune exocrinopathy; cell type; comorbidity; cytokine; defined contribution; eye dryness; functional loss; functional restoration; in vivo; innovation; loss of function; male; mouse model; nanoparticle; normal aging; novel; organ injury; paracrine; prevent; programs; radiation response; response; senescence; side effect; single cell sequencing; stem cell population; suicide gene; therapeutic RNA; tissue degeneration; tissue injury; tumor; wound healing

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.

抽象的 唾液分泌不足可能是由正常衰老过程、放射治疗 (RT) 的副作用以及以下症状引起的： 自身免疫性疾病会导致各种不良后遗症，包括龋齿、口臭和口臭的发生率增加 消化功能下降。干燥综合征 (SS) 是一种影响唾液腺的自身免疫性外分泌病， 0.4% 的美国人口患有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 男女比例）。 SS 的主要缺陷是外分泌腺功能性分泌上皮的丧失。 导致功能丧失的机制是复杂且多因素的，但包括免疫依赖性和 延伸至正常衰老和 RT 的免疫独立病理。细胞衰老是一种重要的肿瘤 抑制机制可以阻止细胞增殖并对伤口愈合产生积极影响，但是当激活时 长期来看，会加剧组织损伤和功能丧失。最近的研究表明，衰老细胞在 SS 患者的唾液腺，由于 RT，以及在正常衰老过程中。细胞衰老如何影响唾液 SS 和其他情况下的功能减退尚不完全清楚。随着年龄的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 破坏组织稳态并导致与年龄相关的病理的蛋白酶。 SASP 与组织有因果关系 旁分泌作用对邻近细胞造成的退化，衰老细胞的基因消融可以保留器官功能 通过限制 SASP。同样，系统性消除衰老细胞的抗衰老药物可以改善整体健康状况并延长寿命 在小鼠中。 SASP 的最小化可能会限制炎症反应的幅度和持续时间，限制炎症反应的损失。 外分泌功能，延缓疾病相关器官衰退。我们已经鉴定出几种控制 SASP 的 microRNA 炎症细胞因子基因表达可作为限制衰老细胞活性的靶标。研究详细 这里将检验以下假设：衰老会促进 SS 样疾病中的非消退性炎症，从而驱动唾液腺 功能减退。我们将通过选择性调节基于类器官的衰老程序和基于类器官的衰老程序来检验我们的假设。 唾液腺功能减退的小鼠模型。我们建议实现以下具体目标： 1. 定义 衰老和干燥综合征相关 miRNA 在 SASP 调节中的贡献。目标 2. 确定是否 消融衰老细胞或靶向促进 SASP 的 miRNA 可以减少未解决的炎症和 体内纤维化。 3. 定义衰老细胞 SASP 对 SS 疾病发展的贡献。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联系的理解。研究比较 用于消除衰老细胞的遗传和 RNA 介导方法以及用于 SASP 表型调节的 antagomirs 揭示了基于 RNA 的潜在治疗策略，用于 SS 患者和其他患者唾液腺功能的恢复 老化或受伤的器官。