Determining Sox10-mediated plasticity in irradiated salivary gland cells

确定受辐射唾液腺细胞中 Sox10 介导的可塑性

• 批准号: 10606665
• 负责人: Christina Elizabeth-Rose Jones
• 金额: $ 5.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-03-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606665
• 关键词: 3-Dimensional; Acinar Cell; Acinus organ component; Acute; Address; Adult; Animal Model; Artificial Saliva; Atrophic; Attenuated; Binding; Bioinformatics; Cell Differentiation process; Cell Line; Cell Lineage; Cell Therapy; Cells; ChIP-seq; Chromatin; Chronic; Clinical; Complex; Cytomegalovirus; Data; Dose; Duct (organ) structure; Ductal Epithelial Cell; Epithelial; Epithelial Cells; Exposure to; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Gene Targeting; Genes; Gland; Goals; Hydration status; Immunoprecipitation; Infusion procedures; Link; Maps; Measures; Mediating; Messenger RNA; Modality; Molecular; Mus; Neural Crest; Neuroglia; Oral health; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plasmids; Process; Proteins; Quality of life; Radiation; Regulator Genes; Reporting; Research; Role; Saliva; Salivary; Salivary Glands; Signal Pathway; Stress; Syndrome; Therapeutic; Time; Tissues; Viral; Xerostomia; adverse outcome; base; fibroblast growth factor receptor 2b; gene network; head and neck cancer patient; in vivo; in vivo evaluation; injury and repair; irradiation; mRNA Expression; novel therapeutics; overexpression; preservation; progenitor; protein expression; radiation effect; repair strategy; repaired; self-renewal; stem; stem cells; tissue regeneration; transcription factor; transcriptome sequencing; translational therapeutics

PROJECT SUMMARY/ABSTRACT Therapeutic irradiation, a commonly used treatment for head and neck cancer patients, irreversibly damages the salivary glands (SGs). Current therapies aim to alleviate the resulting xerostomia (dry mouth syndrome) but fail to address the underlying mechanism of dysfunction, thus new strategies for tissue regeneration are needed. Given that endogenous repair of irradiated SGs is majorly hampered due to the loss of saliva-producing acinar cells and their progenitors, inducing the ability of the remaining ductal cells to behave as acinar progenitors (i.e. plasticity) is an attractive repair strategy. Inducing plasticity is a complex process whereby transcription factors often interact with chromatin modulators, such as Hdac1, to induce downstream gene regulators of progenitor cell potency. Interestingly, it has been shown that some irradiated ductal cells can spontaneously revert towards a progenitor-like state to enable acinar differentiation under severe stress conditions, although too few undergo this transition to fully restore the gland. In order to enhance plasticity, we recently demonstrated that overexpression of transcription factor Sox10 in non-irradiated ductal cells induces plasticity, allowing acinar differentiation ex vivo. However, whether this set-up is applicable to irradiated ductal cells is unclear. Based on preliminary data, we hypothesize that plasticity can be induced in irradiated ductal cells through overexpression of Sox10, which activates a downstream regulatory network through binding with Hdac1. To prove this hypothesis, our objectives are to evaluate the binding capacity of Sox10 to Hdac1, as well as the altered downstream gene network and acinar formation capacity in irradiated cells after inducing a Sox10-mediated plasticity. Overall, these data will then be used to formulate a new translational therapy in our in vivo radiation- induced xerostomia animal model to aid in the repair of SGs post-radiation.

项目摘要/摘要 治疗性放射治疗是头颈部癌症患者的常用治疗方法，它对 唾液腺(SGS)。目前的治疗方法旨在缓解由此产生的口干症(口干综合症)，但失败了。 为了解决功能障碍的潜在机制，因此需要新的组织再生策略。 鉴于受辐射的SGS的内源性修复主要是由于产生唾液的腺泡的丧失而受到阻碍 细胞及其祖细胞，诱导剩余导管细胞表现为腺泡祖细胞的能力(即 可塑性)是一种有吸引力的修复策略。诱导可塑性是一个复杂的过程，转录因子 经常与染色质调节剂，如HDAC1相互作用，诱导祖细胞下游的基因调控 细胞能力。有趣的是，研究表明，一些受辐射的导管细胞可以自发地转化为 一种类似祖细胞的状态，能够在严重的应激条件下实现腺泡分化，尽管太少人经历 这一过渡完全恢复了腺体。为了增强可塑性，我们最近展示了 转录因子Sox10在未照射的导管细胞中过表达诱导可塑性，允许腺泡 体外分化。然而，这种设置是否适用于受辐射的导管细胞尚不清楚。基于 初步数据，我们假设辐射后的导管细胞可以通过过度表达来诱导可塑性。 通过与HDAC1结合激活下游调控网络。为了证明这一点 假设，我们的目标是评估Sox10与HDAC1的结合能力以及改变后的 照射细胞诱导Sox10介导的下游基因网络和腺泡形成能力 可塑性。总而言之，这些数据将被用来在我们的体内放射中制定一种新的翻译疗法-- 诱导口腔干燥症动物模型辅助SGS辐射后修复。