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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.