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Liver Sinusoidal Endothelial Cell Progenitor Cells (sprocs) and Chronic Liver Disease

肝窦内皮细胞祖细胞 (sprocs) 与慢性肝病

基本信息

批准号：
10551832
负责人：
LAURIE D DELEVE
金额：
$ 37.13万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551832
关键词：
Advanced Glycosylation End Products Blood Bone Marrow Capillarity Cardiovascular Diseases Cell Differentiation process Cell Maturation Cell Separation Cells Cerebrovascular Disorders Circulation Cirrhosis Confocal Microscopy Cytometry Data Development Diabetes Mellitus Differentiation Antigens Elements Endothelial Cells Exposure to Fatty Liver Fibrosis Fluorescence Future Goals Hepatic Stellate Cell Hepatocyte Hyperlipidemia Immunohistochemistry Impairment In Situ Hybridization In Vitro Injury Intervention Lead Ligands Lipids Liver Liver Regeneration Location Metabolic syndrome Minor Modeling Molecular Normal Cell Partial Hepatectomy Pathologic Processes Pathway interactions Patients Phenotype Physiological Physiology Play Population Proteins Proteomics Rattus Risk Role Serum Signal Pathway Signal Transduction Source Stream Therapeutic Thioacetamide Tissues acute liver injury cardiovascular risk factor cell type cerebrovascular chronic liver disease chronic liver injury endothelial stem cell fatty liver disease functional disability in vivo intrahepatic liver injury liver repair mortality multi-photon non-alcoholic fatty liver disease novel novel strategies novel therapeutic intervention obese person oxidized low density lipoprotein permissiveness prevent progenitor receptor mediated endocytosis recruit repaired self-renewal single-cell RNA sequencing stem cell niche stem cells uptake

项目摘要

PROJECT SUMMARY The hypothesis for aim 1 is that resident sprocs are the source of liver sinusoidal endothelial cells (LSECs) during normal turnover and that resident sprocs reside in a stem cell niche that promotes their quiescence. Aim 1 will use lineage-tracing to determine whether LSECs are derived from resident sprocs, will characterize LSECs and resident sprocs in-depth to identify cell differentiation markers and lineage markers to determine whether LSECs share common origins with other liver cells, will identify signaling pathways known to respond to known stem cell niche ligands, and will characterize the various ligands and cellular elements that compose the stem cell niche for sprocs. The hypothesis for aim 2 is that changes particular to the metabolic syndrome suppress the NO pathway in LSECs and induce capillarization. This aim will characterize the signaling in NAFLD in isolated LSECs in vitro and in LSECs isolated from NAFLD ex vivo. The hypothesis for aim 3 is that the impaired endocytotic function of BM-derived (“capillarized”) LSECs contributes to aberrant clearance of lipids in NAFLD. Aim 3 will examine uptake of lipids in LSECs taken from rats with NAFLD and will use intravital multiphoton fluorescence confocal microscopy to examine lipid uptake in vivo in rats with NAFLD. Interventions will be used to induce maturation of BM-derived LSECs and studies will examine the effect of this on in vitro and in vivo uptake of lipid. Finally the effect of inducing maturation of BM- derived LSECs on serum lipid level will be compared with the effect of a statin. Collectively, these aims will provide a major advance in our understanding of the role of resident sprocs in liver physiology, which will be critical for future approaches to elicit a greater contribution from resident sprocs to the repair of liver injury and to drive liver regeneration. These studies also have the potential to uncover the mechanisms leading to capillarization in NAFLD as a prelude to providing therapeutic strategies to prevent two consequences of capillarization: the contribution of capillarization to hyperlipidemia and the loss of the ability to suppress hepatic stellate cell activation. Finally, these studies should uncover an important mechanism that contributes to elevated lipid levels in NAFLD with its attendant increased risk of cardiovascular mortality and that may lead to novel approaches to treat this aspect of hyperlipidemia.

项目总结目标1的假设是驻留链状细胞是肝窦内皮细胞(Lsecs)的来源。在正常周转期间，驻留的链状细胞驻留在促进其静止的干细胞利基中。目标 1将使用谱系跟踪来确定LSEC是否源自驻留的sprc，将表征 LSECs和常驻spros深入识别细胞分化标记和谱系标记，以确定 LSEC是否与其他肝细胞有共同的起源，将识别已知的反应信号通路到已知的干细胞利基配体，并将表征组成的各种配体和细胞元件链状细胞的干细胞利基。 Aim 2的假设是，代谢综合征特有的变化抑制了体内的NO途径 LSECs，诱导毛细血管形成。本研究的目的是研究体外分离的LSEC中NAFLD的信号特征。体外分离的非酒精性脂肪肝LSECs。目标3的假设是骨髓来源的(“毛细血管”)LSECs的内吞功能受损有助于NAFLD中脂质的异常清除。目标3将检查LSECs对来自并将使用活体多光子荧光共聚焦显微镜检查大鼠对脂肪的摄取在非酒精性脂肪肝大鼠体内。干预措施将用于诱导骨髓来源的LSEC成熟，研究将检查这对体外和体内脂质摄取的影响。诱导BM成熟的效果。将衍生的LSECs与他汀类药物对血脂水平的影响进行比较。总而言之，这些目标将大大提高我们对驻留链球蛋白在肝脏中的作用的理解。生理学，这对于未来的方法将是至关重要的，以促使常驻spros对修复肝脏损伤，促进肝脏再生。这些研究还有可能揭示导致NAFLD毛细血管形成的机制是提供预防两种疾病的治疗策略的前奏毛细血管化的后果：毛细血管化对高脂血症的贡献和丧失抑制肝星状细胞活化。最后，这些研究应该揭示一个重要的机制，即导致NAFLD的血脂水平升高，并伴随着心血管死亡风险的增加和这可能导致治疗这一方面的高脂血症的新方法。