Latexin in human hematopoietic stem cell expansion

乳胶素在人类造血干细胞扩增中的作用

• 批准号: 9436110
• 负责人: Ying Liang
• 金额: $ 11.48万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-14 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9436110
• 关键词: Behavior; Blood; Blood Cells; Bone Marrow Transplantation; CD34 gene; Cancer Patient; Cell Count; Cell physiology; Cells; Development; Down-Regulation; Genes; Genetic Variation; Goals; Harvest; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune System Diseases; In Vitro; Knockout Mice; Life; Malignant - descriptor; Mediating; Messenger RNA; Modeling; Molecular; National Heart, Lung, and Blood Institute; Nature; PC3.1 antigen; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Physiological; Population; Production; Proteins; Quality of life; Radiation therapy; Recovery; Regenerative Medicine; Regulation; Regulator Genes; Research; Role; Sampling; Savings; Signal Pathway; Stem cell transplant; Stem cells; System; Testing; Therapeutic; Thrombospondin 1; Treatment Efficacy; Umbilical Cord Blood; Variant; Work; Xenograft procedure; base; biobank; in vivo; insight; knock-down; novel; self-renewal; success

PROJECT SUMMARY The goal of this study is to develop new strategies to expand human hematopoietic stem cells (HSC) by utilizing cryopreserved umbilical cord blood (CB) in NHLBI Biorepository. HSC transplantation is currently being used as regenerative medicine for the treatment of congenital deficiencies and malignant diseases of the blood and immune systems. A major roadblock of success of this therapy is the limited number of HSC per harvest and the poorly understood expansion and differentiation behavior. This proposal aims to increase CB HSC ex vivo expansion by targeting a newly identified molecular pathway. Natural genetic diversity offers an important yet largely untapped reservoir for deciphering molecular regulatory mechanisms of HSCs and hematopoiesis. We previously identified the first and probably so far the only stem cell regulatory gene, latexin (Lxn), by employing genetic diversity approach. Lxn is a negative regulator of HSC number and function. Our preliminary work in Lxn knockout mice showed that Lxn inactivation increases HSC numbers, and the expansion is controlled within the physiological range of variation. The expanded HSCs maintain the capacity of self-renewal and multilineage differentiation. Considering the nature of Lxn as a natural variant regulator of HSCs, we speculate that Lxn may function similarly in human population. Our preliminary studies demonstrate the negative correlation between HSC numbers and Lxn expression in human samples. We therefore hypothesize that Lxn negatively regulates human HSCs, and its inhibition leads to HSC expansion by increasing self-renewal while maintaining multi-lineage differentiation capacity. Specific aims are to: 1) determine whether knockdown of Lxn can expand human HSCs while maintaining their self-renewal and multilineage differentiation capacity, and 2) Determine the molecular mechanisms by which Lxn-Thbs1 signaling pathway regulates human HSC expansion and function. This research will provide new insight into the potential utility of Lxn inhibition to promote HSC expansion, thereby benefiting patients needing HSC transplantation.

项目摘要 本研究的目的是开发新的策略来扩增人造血干细胞（HSC）， 利用NHLBI生物库中冷冻保存的脐带血（CB）。HSC移植目前 被用作治疗先天性缺陷和恶性疾病的再生医学， 血液和免疫系统。这种疗法成功的一个主要障碍是每个人的HSC数量有限。 收获和知之甚少的扩张和分化行为。这项建议旨在增加CB 通过靶向新鉴定的分子途径进行HSC离体扩增。自然遗传多样性提供了 重要的但在很大程度上尚未开发的水库，用于破译HSC的分子调控机制， 造血我们之前发现了第一个，也可能是迄今为止唯一的干细胞调控基因，latexin (Lxn)采用遗传多样性方法。Lxn是HSC数量和功能的负调节因子。我们 Lxn基因敲除小鼠的初步研究表明，Lxn失活增加了HSC的数量， 膨胀被控制在生理变化范围内。扩展的HSC保持容量 自我更新和多谱系分化。考虑到Lxn作为天然变体调节因子的性质 我们推测Lxn可能在人类群体中具有类似的功能。我们的初步研究表明 人类样本中HSC数量与Lxn表达之间呈负相关。因此我们 假设Lxn负调节人HSC，其抑制导致HSC扩增， 增加自我更新，同时保持多谱系分化能力。具体目标是：1） 确定Lxn的敲低是否可以扩增人HSC，同时维持它们的自我更新， 多系分化能力，以及2）确定Lxn-Thbs 1 信号通路调节人HSC的扩增和功能。这项研究将提供新的见解， Lxn抑制促进HSC扩增的潜在效用，从而使需要HSC的患者受益 移植