Lacrimal Gland Repair Using Progenitor Cells

使用祖细胞修复泪腺

• 批准号: 10661511
• 负责人: Helen P. Makarenkova
• 金额: $ 41.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661511
• 关键词: Acinar Cell; Acinus organ component; Acute; Adult; Affect; American; Anti-Inflammatory Agents; Autoimmune; Blurred vision; Caspase; Cell Differentiation process; Cell Lineage; Cell Polarity; Cell Transplantation; Cell physiology; Cells; Cellular biology; Chronic; Data; Development; Disease; Disease model; Dry Eye Syndromes; Dryness; Engraftment; Epithelial Cells; Etiology; Eye Infections; Eye diseases; Film; Fluids and Secretions; Functional disorder; Gene Expression; Genes; Genetic; Gland; Glycoproteins; Human; IL18 gene; Impairment; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Ion Channel; Label; Lacrimal gland structure; Link; Lymphocytic Infiltrate; Maintenance; Mediating; Molecular; Multiprotein Complexes; Mus; Myoepithelial cell; Natural regeneration; Nature; Organ; Pathway interactions; Production; Publishing; RNA Interference; Recovery of Function; Reserve Cell; Reserve Stem Cell; Risk; Role; Sjogren' s Syndrome; Stem cell transplant; Symptoms; System; Testing; Therapeutic; Thrombospondin 1; Time; Tissues; Transplantation; United States; aqueous; cell replacement therapy; cytokine; density; diphtheria toxin fragment A; donor stem cell; effective therapy; epithelial stem cell; experimental study; eye dryness; functional improvement; functional restoration; improved; in vivo; injured; mouse model; novel strategies; novel therapeutics; postnatal; progenitor; promoter; regenerative cell; repaired; response; stem; stem cell function; stem cell niche; stem cell therapy; stem cells; symptom treatment; targeted treatment

Lacrimal gland (LG) is an exocrine tubuloacinar gland that secretes the aqueous layer of the tear film. Any alteration in the quantity and/or quality of tears produced by LG can result in aqueous deficiency dry eye disease (ADDE). ADDE is a chronic condition affecting millions of Americans, with symptoms ranging from a dry itchiness to blurred vision and accompanied by an increased risk of eye infections. Regenerative and stem cell therapies that target LG repair are now coming to the fore, however, our understanding of LG stem and progenitor cell biology is still incomplete. Our previous experiments on progenitor cell transplantation label retaining cell (LRC) analysis and cell lineage tracing with clonal analyses suggest adult LG has reserve or extremely plastic progenitor cells especially in the Sox10+ cell lineage and that LG progenitor may have a therapeutic role in ADDE. Our recent studies demonstrate that myoepithelial cells (MECs) retained high level of plasticity and are able to differentiate into acinar cells upon LG injury or transplantation. Moreover, genetic elimination of MECs in vivo showed that they are required for LG progenitor and acinar cell function. We also showed that LG inflammation could be mediated by the Pannexin-1 (Panx1) membrane channel glycoprotein - a key regulator of inflammasome assembly. Inflammasomes are large intracellular multiprotein complexes that activate proinflammatory cytokines in response to infection and tissue damage or chronic inflammation. Our study suggests that the epithelial cells sense damage/inflammation and contribute to the inflammatory response by producing the pro- inflammatory cytokines interleukin-1 Beta(IL-1Beta) and IL-18. Moreover, we showed that blocking pannexin-1 (Panx1) or Caspase 4 in LG reduces pro-inflammatory cytokine release and improves transplanted cell engraftment. In a new proposal we will study the molecular and cellular nature of LG progenitor and surrounding differentiated cells in healthy and chronically inflamed LG. First we will evaluate the Sox10+ (MEC and acinar) lineage establishment in healthy and diseased LGs and investigate the role Sox10 expression in Krt5 expressing progenitors in establishment of the MEC lineage. Second, we will investigate the role of inflammasome pathways in LG progenitor and other epithelial cell function and LG repair in SS mouse models Third, we will use a combination of anti-inflammatory Panx1 pathways blocking therapies and cell transplantation for LG repair. We expect to identify key mechanisms responsible for LG dysfunction. Our analysis of inflammasome pathways may facilitate development of entirely new drug treatments for ADDE. Our studies will also provide important enabling information for use of LG progenitor cells in cell replacement therapy for dry eye diseases that have no effective treatment or cure.

泪腺（LG）是一种外分泌管状腺体，分泌泪膜的水层。 LG 产生的眼泪的数量和/或质量的任何变化都可能导致水液缺乏、干燥 眼病（ADDE）。 ADDE 是一种影响数百万美国人的慢性疾病，其症状包括 从干痒到视力模糊，并伴有眼部感染风险增加。再生性 针对 LG 修复的干细胞疗法现在已崭露头角，然而，我们对 LG 的理解 干细胞和祖细胞生物学仍然不完整。我们之前对祖细胞的实验 移植标记保留细胞 (LRC) 分析和细胞谱系追踪与克隆分析表明成人 LG 拥有储备或极具可塑性的祖细胞，尤其是在 Sox10+ 细胞谱系中，并且 LG 祖细胞可能对 ADDE 具有治疗作用。我们最近的研究表明肌上皮细胞 （MEC）保留了高水平的可塑性，并且能够在 LG 损伤或 移植。此外，体内 MEC 的基因消除表明它们是 LG 所必需的。 祖细胞和腺泡细胞功能。我们还表明 LG 炎症可能是由 Pannexin-1 (Panx1) 膜通道糖蛋白 - 炎症小体组装的关键调节因子。 炎症小体是大型细胞内多蛋白复合物，可激活促炎细胞因子 对感染和组织损伤或慢性炎症的反应。我们的研究表明，上皮细胞 细胞感知损伤/炎症并通过产生促炎症反应来促进炎症反应 炎症细胞因子白细胞介素-1 Beta (IL-1Beta) 和 IL-18。此外，我们发现阻断 pannexin-1 LG 中的 (Panx1) 或 Caspase 4 可减少促炎细胞因子的释放并改善移植细胞 植入。在一项新提案中，我们将研究 LG 祖细胞和细胞的分子和细胞性质 健康和慢性发炎的 LG 周围的分化细胞。首先我们将评估Sox10+ （MEC 和腺泡）健康和患病 LG 中的谱系建立并研究 Sox10 的作用 MEC谱系建立过程中Krt5表达祖细胞的表达。其次，我们将调查 炎症小体通路在 LG 祖细胞和其他上皮细胞功能以及 SS 中 LG 修复中的作用 小鼠模型 第三，我们将使用抗炎 Panx1 通路阻断疗法的组合 以及用于 LG 修复的细胞移植。我们期望找出导致 LG 功能障碍的关键机制。 我们对炎症小体途径的分析可能有助于开发全新的药物治疗方法 添加。我们的研究还将为在细胞中使用 LG 祖细胞提供重要的支持信息。 没有有效治疗或治愈方法的干眼病的替代疗法。

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