Development of Robust Culture Systems for the Human Splenic Littoral Cell

人脾滨细胞稳健培养系统的开发

• 批准号: 8604140
• 负责人: JOYCE DIANE FINGEROTH
• 金额: --
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604140
• 关键词: Antigen-Antibody Complex; Antigens; Apoptotic; Appearance; Autoimmune Diseases; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Blood flow; Bypass; CD8 Antigens; Cell Culture System; Cell Line; Cell Nucleus; Cell physiology; Cells; Cellular biology; Communicable Diseases; Complex; Cytoplasm; Cytoplasmic Filaments; Deposition; Development; Discontinuous Capillary; Disease; Distant; Endothelial Cells; Evolution; Filtration; Foundations; Future; Gene Proteins; Growth; Heart Diseases; Hematopoietic; Hemoglobinopathies; Hemolytic Anemia; Hemosiderin; Human; Immune; Immune system; Immunologics; Immunologist; Immunology; In Situ; Individual; Infection; Infectious Agent; Investigation; Laboratories; Lead; Left; Leukocytes; Lymphatic System; Lysosomes; Malaria; Malignant Neoplasms; Malpighian corpuscles; Mammals; Mediator of activation protein; Methods; Mus; Necrosis; Organ; Pathologist; Pathology; Persons; Phagocytes; Phagocytosis; Population; Primates; Procedures; Process; Proteins; RNA; Regulation; Research Methodology; Risk; Sepsis; Sinus; Site; Smooth Muscle; Spleen; Splenic Red Pulp; Splenocyte; Stress Fibers; Structure; System; Therapeutic; Ursidae Family; Venous; Vesicle; Work; base; lymph nodes; macrophage; man; monocyte; mortality; neoplastic cell; novel; pathogen; preclinical study; prevent; protein expression; public health relevance; repaired; success; therapeutic development; trafficking; venous sinus

DESCRIPTION (provided by applicant): The spleen is the largest secondary immune system organ in man. Individuals who are asplenic die at an increased rate from overwhelming sepsis. They are also at greater risk of autoimmune disease, some cancers and ischemic cardiac disease. Enhanced mortality is attributed to lack of phagocytes sequestered in spleen that efficiently eliminate appropriate targets, though related cells can be found at other sites. Although the overall organization of splenic white pulp is similar to that of lymph nodes, spleen is not connected to the lymphatic system. Instead, pathogens, RBCs, apoptotic/necrotic, altered and tumor cells all are delivered to and leave the spleen in blood. In contrast to white pulp, splenic red pulp serves as both a reservoir and a filter that determines whether cells coursing therein are retained, destroyed or returned to the circulation. The human venous sinus-lining cell, known as the littoral cell (LC), comprises ~30% of red pulp. Increasing evidence indicates these highly specialized splenocytes are the major determinant of whether RBCs and others are destroyed, retained or returned to the circulation, though the mechanisms that regulate their function are entirely unknown. Others and we showed that LCs are not a classical endothelial cells as they bear multiple macrophage and smooth muscle-associated antigens, are CD8+ and lack traditional markers of endothelial and also hematopoietic lineage. So, why is so little known about LC function? The acquisition, purification and culture of LCs have historically proved very difficult. Based on our recent success in obtaining fresh spleen as well as identifying markers that distinguish LCs from other splenocytes, we are now prepared to further isolate and profile LC gene/protein expression (AIM I). Although cells such as LCs that form specialized structures within complex organs are often hard to propagate ex vivo, overcoming these limitations would represent a significant advance in understanding LC function(s). We have assembled a group of expert endothelial cell biologist-immunologists, and pathologists who will provide us with in depth guidance as we develop diverse LC culture systems (AIM II) that are both physiologically relevant and tractable. These methods will enable discovery of the mechanisms that underlie LC function and lead to development of therapeutics able to modulate splenic filtration in different disease states (e.g. sepsis, malaria, hemoglobinopathies and others).

描述（由申请人提供）：脾脏是人体最大的次级免疫系统器官。无脾患者死于严重脓毒症的几率更高。他们患自身免疫性疾病、某些癌症和缺血性心脏病的风险也更大。死亡率增加是由于脾脏中缺乏有效消除适当靶标的吞噬细胞，尽管在其他部位也可以找到相关细胞。虽然脾脏白髓的整体组织与淋巴结相似，但脾脏并不与淋巴系统相连。相反，病原体、红细胞、凋亡/坏死细胞、变异细胞和肿瘤细胞都被输送到血液中并离开脾脏。与白髓相反，脾红髓既充当储存器又充当过滤器，确定在其中流动的细胞是否被保留、破坏或返回循环。人类静脉窦内壁细胞，称为滨细胞 (LC)，约占红髓的 30%。越来越多的证据表明，这些高度特化的脾细胞是红细胞和其他细胞是否被破坏、保留或返回循环的主要决定因素，尽管调节其功能的机制完全未知。其他人和我们表明，LC 不是经典的内皮细胞，因为它们具有多种巨噬细胞和平滑肌相关抗原，是 CD8+ 并且缺乏内皮和造血谱系的传统标记。那么，为什么人们对 LC 功能知之甚少呢？历史证明，LC 的获取、纯化和培养非常困难。基于我们最近成功获得新鲜脾脏以及识别区分 LC 与其他脾细胞的标记，我们现在准备进一步分离和分析 LC 基因/蛋白表达 (AIM I)。尽管像 LC 这样在复杂器官内形成特殊结构的细胞通常很难离体繁殖，但克服这些限制将代表着理解 LC 功能的重大进步。我们组建了一组内皮细胞生物学家、免疫学家和病理学家专家，他们将为我们开发生理相关且易于处理的多种 LC 培养系统 (AIM II) 提供深入指导。这些方法将有助于发现 LC 功能的机制，并导致开发能够在不同疾病状态（例如脓毒症、疟疾、血红蛋白病等）下调节脾脏滤过的治疗方法。