Lacrimal Gland Repair Using Progenitor Cells

使用祖细胞修复泪腺

• 批准号: 10436876
• 负责人: Helen P. Makarenkova
• 金额: $ 39.77万
• 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/10436876
• 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; Engraftment; Epithelial Cells; Etiology; Eye Infections; Eye diseases; Film; Fluids and Secretions; Functional disorder; Gene Expression; Genes; Genetic; Gland; Glycoproteins; Human; Impairment; Infection; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-18; Ion Channel; Label; Lacrimal gland structure; Link; Lymphocyte; Maintenance; Mediating; Molecular; Multiprotein Complexes; Mus; Myoepithelial cell; Natural regeneration; Nature; Organ; Pathway interactions; Production; Publishing; RNA Interference; Recovery of Function; Reserve Cell; Risk; Role; Sjogren' s Syndrome; Stem cell transplant; Symptoms; System; Testing; Therapeutic; Thrombospondin 1; Time; Tissues; Transplantation; United States; aqueous; base; cell replacement therapy; cytokine; density; diphtheria toxin fragment A; donor stem cell; effective therapy; epithelial stem cell; experimental study; eye dryness; functional restoration; improved; improved functioning; in vivo; injured; mouse model; novel strategies; novel therapeutics; postnatal; progenitor; promoter; regenerative cell; repaired; response; stem; stem cell function; 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）是一种分泌泪膜水层的外分泌管泡腺。 由LG产生的泪液的数量和/或质量的任何改变都可能导致干性水缺乏症。 眼病（ADDE）。ADDE是一种影响数百万美国人的慢性疾病，症状包括 从干痒到视力模糊，并伴有眼部感染的风险增加。再生 针对LG修复的干细胞疗法现已崭露头角，然而，我们对LG的了解 干细胞和祖细胞生物学仍不完善。我们之前的祖细胞实验 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具有储备或极可塑的祖细胞，特别是在Sox 10+细胞谱系中，并且LG 祖细胞可能在ADDE中具有治疗作用。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，并能够在LG损伤后分化为腺泡细胞， 移植此外，体内MEC的遗传消除表明它们是LG所必需的。 祖细胞和腺泡细胞功能。我们还发现，LG炎症可以通过 Pannexin-1（Panx 1）膜通道糖蛋白-炎症小体组装的关键调节因子。 炎性小体是细胞内的大的多蛋白复合物，其在细胞内激活促炎细胞因子。 对感染和组织损伤或慢性炎症的反应。我们的研究表明， 细胞感知损伤/炎症，并通过产生促炎症反应的蛋白质来促进炎症反应。 炎性细胞因子白细胞介素-1 β（IL-1 β）和IL-18。此外，我们发现阻断泛连接蛋白-1 LG中的Panx 1或Caspase 4减少促炎细胞因子释放并改善移植细胞 移植在一项新提案中，我们将研究LG祖细胞的分子和细胞性质， 首先，我们将评估Sox 10+细胞在健康和慢性炎症LG周围的分化细胞。 (MEC和腺泡）谱系建立，并研究Sox 10 在MEC谱系的建立中表达Krt 5的祖细胞中的表达。第二，我们会调查 炎症体通路在LG祖细胞和其他上皮细胞功能及SS中LG修复中作用 第三，我们将使用抗炎Panx 1通路阻断疗法的组合 和细胞移植来修复LG。我们希望确定负责LG功能障碍的关键机制。 我们对炎性体通路的分析可能有助于开发全新的药物治疗方法， ADDE.我们的研究也将为LG祖细胞在细胞中的应用提供重要的使能信息。 干眼病的替代疗法，没有有效的治疗或治愈。