Senescence and Salivary Gland Dysfunction

衰老和唾液腺功能障碍

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的衰老可能是由于正常的衰老过程，放射治疗（RT）的副作用以及一种症状自身免疫性疾病导致多种阴性后遗症，包括龋齿的发生率增加降低的消化功能。 Sjögren's综合征（SS）是一种影响唾液网格的自身免疫性外分泌病，美国人群中0.4％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 女性与男性比例）。 SS的主要赤字是外分泌网格中功能秘书上皮的丧失。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免疫独立的病理，延伸至正常衰老和RT。细胞感应是重要的肿瘤约束一半的细胞增殖机制，对伤口愈合产生积极影响，但是当激活时长期以来，会加剧组织损伤和功能丧失。最近的工作表明，感觉细胞积累由于RT和正常衰老期间，SS患者的唾液腺。细胞感应如何有助于唾液 SS和其他条件中的功能障碍尚不完全理解。随着年龄而积聚的衰老细胞采用感应相关的秘书表型（SASP），其特征是细胞因子，生长因子和破坏组织体内稳态并导致与年龄相关的病理的蛋白酶。 SASP有时与组织有关旁分泌作用对邻近细胞的变性，而感觉细胞的遗传消融可以保留器官功能通过限制SASP。同样，从系统地消除感觉细胞的鼻溶剂可以增加一般健康和寿命在老鼠中。 SASP最小化可能会限制炎症反应的放大器和持续时间，限制外分泌功能，延迟与疾病相关的器官下降。我们已经确定了几种控制SASP和的microRNA 炎性细胞因子基因表达，可用作限制感觉细胞活性的靶标。研究详细介绍了这里将检验以下假设：感应促进类似SS样疾病的非分辨感染以驱动唾液腺功能障碍。我们将通过选择性调制基于器官和基于器官和唾液腺功能障碍的鼠模型。我们建议解决以下特定目标：1。定义 SASP调节中感应 - 和Sjögren综合征相关的miRNA的贡献。目标2。确定是否消融感觉细胞或靶向miRNA促进SASP的靶向可以减少非分解注入，并且体内纤维化。 3。定义Sensent细胞SASP对SS疾病发展的贡献。这项研究将进一步我们对感应，感染和唾液腺功能低下之间的联系的理解。研究比较遗传和RNA介导的感觉细胞消除和Antagomirs的SASP表型调节方法将揭示了潜在的基于RNA的治疗策略，用于恢复SS患者和其他的唾液腺的功能恢复老化或受伤的器官。