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）是分泌泪液膜水层的外分泌管状腺。