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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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），对于细胞和基因治疗是有意义的，因为它们可以容易地从患者获得，在培养物中扩增，使用或不使用病毒进行基因工程，然后返回用于同一患者的治疗。它们也是令人感兴趣的，因为它们可以找到受损组织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，在非人灵长类动物中进行的细胞的广泛试验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显然是必不可少的。该提案的目标是： 具体目标。比较灵长类动物MSC与人MSC在体内在全身或颅内输注到免疫缺陷小鼠后植入多种组织的能力。这些研究目前正在进行中。我们使用立体定位递送将人和恒河猴骨髓和脂肪组织来源的MSC注射到NIH III和Twitch（受Krabbe影响的）小鼠的CNS中。我们目前正在评估这些细胞在CNS中的植入和分化。来自免疫缺陷小鼠的数据表明，细胞移植，持续长达180天，并沿着沿着神经谱系进行中度分化。目前正在收集将MSC（来源于骨髓和脂肪组织）直接注射到Twitch小鼠脑的侧脑室中。到目前为止，我们已经证明了一个统计学显着增加的寿命在克拉伯影响的动物。细胞介导这种效应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，如多发性硬化症和II型糖尿病。