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）是一种外分泌微管腺，分泌泪膜的水层。 LG产生的眼泪的数量和/或质量的任何改变都会导致缺乏水。 眼病（加法）。 adde是一种慢性病，影响了数百万美国人，症状范围为 从干燥的视力到视力模糊，并伴随着眼部感染的风险增加。再生 但是，靶向LG修复的干细胞疗法现在即将出现，但是我们对LG的理解 茎和祖细胞生物学仍然不完整。我们以前关于祖细胞的实验 通过克隆分析的移植标签保留细胞（LRC）分析和细胞谱系跟踪表明成年 LG具有储备或极端塑料祖细胞，尤其是在Sox10+细胞谱系中，LG 祖先在另外可能具有治疗作用。我们最近的研究表明肌上皮细胞 （MEC）保留高水平的可塑性，并能够在LG损伤或 移植。此外，在体内消除MEC的遗传表明是LG所必需的 祖细胞和腺泡细胞功能。我们还表明，LG炎症可以由 Pannexin -1（PANX1）膜通道糖蛋白 - 炎性体组装的关键调节剂。 炎症是大型细胞内多蛋白络合物，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 细胞感知损害/炎症，并通过产生促进作用，从而导致炎症反应 炎性细胞因子白介素-1β（IL-1BETA）和IL-18。此外，我们表明阻止Pannexin-1 （PANX1）或LG中的caspase 4减少促炎细胞因子释放并改善移植细胞 植入。在一个新提案中，我们将研究LG祖细胞和细胞的分子和细胞性质 在健康和长期发炎的LG中周围分化细胞。首先，我们将评估Sox10+ （MEC和ACINAR）在健康和患病的LGS中建立谱系，并研究SOX10的角色 在建立MEC谱系的KRT5中表达祖细胞的表达。第二，我们将调查 炎性体途径在LG祖细胞和其他上皮细胞功能以及SS中LG修复中的作用 鼠标模型第三，我们将使用抗炎panx1途径的组合阻塞疗法 和细胞移植以进行LG修复。我们希望确定负责LG功能障碍的关键机制。 我们对炎性途径的分析可能有助于开发全新的药物治疗 加。我们的研究还将提供重要的启示信息，用于使用LG祖细胞在细胞中 无效治疗或治愈的干眼疾病的替代疗法。

项目成果

The Divergent Pattern of SARS-CoV-2 Variant Predominance and Transmission Dynamics in the Brazilian Island of Ilhabela.

• DOI: 10.3390/v14071481
• 发表时间: 2022-07-05
• 期刊: Viruses

Identification of Immunogenic Linear B-Cell Epitopes in C. burnetii Outer Membrane Proteins Using Immunoinformatics Approaches Reveals Potential Targets of Persistent Infections.

• DOI: 10.3390/pathogens10101250
• 发表时间: 2021-09-28
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Fontes SDS;Maia FM;Ataides LS;Conte FP;Lima-Junior JDC;Rozental T;da Silva Assis MR;Júnior AAP;Fernandes J;de Lemos ERS;Rodrigues-da-Silva RN
• 通讯作者: Rodrigues-da-Silva RN

High Catalytic Activity of Lipase from Yarrowia lipolytica Immobilized by Microencapsulation.

• DOI: 10.3390/ijms19113393
• 发表时间: 2018-10-30
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: da S Pereira A;L Fraga J;M Diniz M;C Fontes-Sant'Ana G;F F Amaral P
• 通讯作者: F F Amaral P

Turnover of SARS-CoV-2 Lineages Shaped the Pandemic and Enabled the Emergence of New Variants in the State of Rio de Janeiro, Brazil.

• DOI: 10.3390/v13102013
• 发表时间: 2021-10-07
• 期刊: Viruses
• 作者: Francisco Junior RDS;Lamarca AP;de Almeida LGP;Cavalcante L;Machado DT;Martins Y;Brustolini O;Gerber AL;Guimarães APC;Gonçalves RB;Alves C;Mariani D;Cruz TF;de Souza IV;de Carvalho EM;Ribeiro MS;Carvalho S;da Silva FD;Garcia MHO;de Souza LM;da Silva CG;Ribeiro CLP;Cavalcanti AC;de Mello CMB;Struchiner CJ;Tanuri A;de Vasconcelos ATR
• 通讯作者: de Vasconcelos ATR

Anticancer Activity and Molecular Targets of Piper cernuum Substances in Oral Squamous Cell Carcinoma Models.

• DOI: 10.3390/biomedicines11071914
• 发表时间: 2023-07-06
• 期刊: Biomedicines
• 影响因子: 4.7