Defining the Earliest Stages of Lymphoid Commitment in Human Bone Marrow

定义人骨髓中淋巴组织的最早阶段

• 批准号: 8317039
• 负责人: Lisa Ann Kohn
• 金额: $ 3.38万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317039
• 关键词: Address; Adult; B-Lymphocytes; Biological Assay; Bone Marrow; CD34 gene; Cell Culture Techniques; Cell Maintenance; Cells; Characteristics; Clinical; Coculture Techniques; Common Lymphoid Progenitor; Competence; Data; Development; Diagnostic; Disease; Engineering; Erythroid; Flow Cytometry; Gene Expression; Gene Expression Profile; Generations; Genes; Goals; Hematopoietic stem cells; Home environment; Homing; Human; Human Biology; Immune; Immune system; In Vitro; Infection; Knowledge; L-Selectin; Life; Ligands; Lymphoid; Lymphoid Cell; Lymphopoiesis; MME gene; Malignant Neoplasms; Modeling; Molecular; Molecular Profiling; Mus; Myelogenous; Natural Killer Cells; Outcome; Output; Pathway interactions; Patients; Population; Population Heterogeneity; Process; Production; Recovery; Relative (related person); Reporting; Research Proposals; SELL gene; Staging; Stem cell transplant; Stem cells; Surface Antigens; System; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Transplantation; Umbilical Cord Blood; Work; chemokine receptor; clinically relevant; comparative; immune function; improved; in vitro Assay; in vivo; killer T cell; notch protein; population based; progenitor; reconstitution; restoration

DESCRIPTION (provided by applicant): A large number of reports continue to refine the differentiation stages of murine lymphopoiesis. However very little is known about the earliest stages of human lymphoid differentiation, those few reports that exist have mostly used umbilical cord blood. The studies in this research proposal will address a critical gap in our knowledge of adult human lymphopoiesis, through the identification and characterization of the most primitive lymphoid progenitors in the human bone marrow able to generate T cells. The overall goal of these studies is to identify the lymphoid progenitors in adult human bone marrow with maximum T cell production capacity. We have identified a progenitor population in human bone marrow that expresses high levels of the homing molecule L-selectin (CD62L) and possesses robust lymphoid potential in vitro. We hypothesize that this CD34+ CD10- CD62L++ ("CD10-") lymphoid-restricted progenitor population marks the first stage of commitment by human hematopoietic stem cells to the lymphoid differentiation pathway. Further, we propose that the CD10- population is a more primitive precursor with superior T lymphoid potential to the previously described CD34+ CD10+ ("CD10+") LP population in human bone marrow. The studies in Aim 1 address the biology of human lymphoid commitment by defining the molecular characteristics of the CD10- and CD10+ LPs. These studies define the lineage relationship between the two LP populations based on their gene expression profiles, both globally and specifically using genes that are known to be critical to lymphoid development. The studies in Aim 2 address clinical relevance by determining the ability of the CD10- and CD10+ LPs to home and reconstitute the thymus and by quantifying the relative functional output of T cells from each population using in vitro assays and in vivo using a xenogeneic transplant model. This knowledge is essential for the development of diagnostic and therapeutic advances toward the process of lymphoid differentiation and thymic reconstitution. PUBLIC HEALTH RELEVANCE: This proposal will examine how the immune system develops from stem cells in the bone marrow of humans during adult life. These studies will increase our knowledge of how the cells of the immune system can be isolated and manipulated in order to improve outcomes by decreasing infections after hematopoietic stem cell transplant.

描述（由申请人提供）：大量报告不断完善小鼠淋巴细胞生成的分化阶段。然而，人们对人类淋巴分化的最早阶段知之甚少，现有的少数报告大多使用脐带血。本研究计划中的研究将通过鉴定和表征人类骨髓中能够生成 T 细胞的最原始淋巴祖细胞，解决我们对成人淋巴细胞生成知识的一个关键空白。这些研究的总体目标是鉴定成人骨髓中具有最大 T 细胞生产能力的淋巴祖细胞。我们在人骨髓中鉴定出一个祖细胞群，其表达高水平的归巢分子 L-选择素 (CD62L)，并在体外具有强大的淋巴潜能。我们假设这种 CD34+ CD10- CD62L++ (“CD10-”) 淋巴限制性祖细胞群标志着人类造血干细胞进入淋巴分化途径的第一阶段。此外，我们提出，CD10-群体是更原始的前体，具有比先前描述的人骨髓中的CD34+CD10+（“CD10+”）LP群体更优越的T淋巴潜能。目标 1 中的研究通过定义 CD10- 和 CD10+ LP 的分子特征来解决人类淋巴定型的生物学问题。这些研究根据基因表达谱定义了两个 LP 群体之间的谱系关系，无论是全球性的还是专门使用已知对淋巴发育至关重要的基因。目标 2 中的研究通过确定 CD10- 和 CD10+ LP 归巢和重建胸腺的能力，并通过使用体外测定和体内异种移植模型量化每个群体的 T 细胞的相对功能输出来解决临床相关性。这些知识对于淋巴分化和胸腺重建过程的诊断和治疗进展至关重要。 公共健康相关性：该提案将研究成年后人类骨髓中的干细胞如何发育成免疫系统。这些研究将增加我们对如何分离和操纵免疫系统细胞的了解，以便通过减少造血干细胞移植后的感染来改善结果。