Saturday, July 27, 2024
7/27/2024
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.
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