BIOLOGY OF NON-HUMAN PRIMATE MARROW STROMAL CELLS

非人灵长类动物骨髓基质细胞的生物学

• 批准号: 8358037
• 负责人: Bruce A. Bunnell
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358037
• 关键词: Adipose tissue; Affect; Alzheimer' s Disease; Animal Model; Animals; Biology; Bone Marrow; Brain; Cell Differentiation process; Cell Therapy; Cells; Child; Clinical Trials; Data; Disease; Engineering; Engraftment; Funding; Goals; Grant; Heart failure; Home environment; Human; Immune; Immunodeficient Mouse; Inflammatory; Infusion procedures; Injection of therapeutic agent; Longevity; Macaca mulatta; Marrow; Mediating; Mesenchymal Stem Cells; Multiple Sclerosis; Mus; National Center for Research Resources; Non-Insulin-Dependent Diabetes Mellitus; Osteoporosis; Parkinsonian Disorders; Pathway interactions; Patients; Primates; Principal Investigator; Procedures; Rare Diseases; Research; Research Infrastructure; Resources; Source; Stromal Cells; Testing; Tissues; United States National Institutes of Health; Virus; adult stem cell; cell injury; cost; gene therapy; human disease; in vivo; interest; lateral ventricle; leukodystrophy; nonhuman primate; relating to nervous system

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall aim of the project is to develop procedures whereby adult stem cells from the bone marrow stroma can be used for trials of gene therapy in non-human primates. The adult stem cells, referred to as mesenchymal stem cells or marrow stromal cells (MSCs), are of interest for cell and gene therapy because they can readily be obtained from a patient, expanded in culture, genetically engineered with or without the use of viruses, and then returned for therapy of the same patient. They are also of interest because they home to damaged tissues and differentiate to replace the damaged cells in the tissues. The cells are currently being tested in many small animal models of human diseases and several promising clinical trials with the cells have been initiated in rare diseases in children. However, extensive trials of the cells in non-human primates are clearly essential for some of the currently proposed applications to common diseases such as osteoporosis, cardiac failure, Parkinsonism, leukodystrophies, and Alzheimer's disease. The goals of the proposal are: Specific Aim. Compare the primate MSCs to human MSCs in vivo in their ability to engraft into multiple tissues after systemic or intracranial infusion into immunodeficient mice. These studies are currently ongoing. We have injected human and rhesus bone marrow and adipose tissue derived MSCs into the CNS of NIHIII and Twitcher (Krabbe-affected) mice, using stereotaxic delivery. We are currently assessing engraftment and differentiation of these cells in the CNS. Data from the immune deficient mice indicate the cells engraft, persist for as long as 180 days and undergo moderate differentiation along neural lineages. Direct injection of MSCs (derived from bone marrow and adipose tissue) into the lateral ventricles of the brains of Twitcher mice is currently being collected. To date, we have demonstrated a statistically significant increase in life span in Krabbe-affected animals. The primary mechanisms by which the cells appear to mediate the effect is through suppression of the inflammatory pathways associated with the disease. We have also begun applying these cells for other diseases such as Multiple Sclerosis and Type II diabetes.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该项目的总体目标是开发程序，使来自骨髓基质的成体干细胞可用于非人类灵长类动物的基因治疗试验。成体干细胞，称为间充质干细胞或骨髓基质细胞（MSC），对细胞和基因治疗很有意义，因为它们可以很容易地从患者身上获得，在培养物中扩增，在使用或不使用病毒的情况下进行基因工程，然后返回对同一患者进行治疗。它们之所以引起人们的兴趣，还因为它们以受损组织为家，并分化以取代组织中受损的细胞。 这些细胞目前正在许多人类疾病的小动物模型中进行测试，并且已经在儿童罕见疾病中启动了几项有希望的细胞临床试验。然而，在非人类灵长类动物中对这些细胞进行广泛的试验显然对于目前提出的一些常见疾病（如骨质疏松症、心力衰竭、帕金森病、脑白质营养不良和阿尔茨海默病）的应用至关重要。该提案的目标是： 具体目标。比较灵长类 MSC 与人类 MSC 在全身或颅内输注至免疫缺陷小鼠后植入多个组织的能力。这些研究目前正在进行中。我们使用立体定向递送将人类和恒河猴骨髓和脂肪组织来源的 MSC 注射到 NIHIII 和 Twitcher（Krabbe 感染）小鼠的中枢神经系统中。我们目前正在评估这些细胞在中枢神经系统中的植入和分化。来自免疫缺陷小鼠的数据表明，细胞植入后可持续长达 180 天，并沿着神经谱系进行适度分化。目前正在收集将 MSC（源自骨髓和脂肪组织）直接注射到 Twitcher 小鼠大脑侧脑室中的方法。迄今为止，我们已经证明受克拉布影响的动物的寿命在统计上显着延长。细胞介导这种作用的主要机制是通过抑制与疾病相关的炎症途径。我们还开始将这些细胞应用于其他疾病，例如多发性硬化症和二型糖尿病。