NONHUMAN PRIMATE MODEL FOR KRABBE'S DISEASE

克拉伯病的非人类灵长类动物模型

基本信息

批准号：
8358078
负责人：
Bruce A. Bunnell
金额：
$ 3.72万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
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/8358078
关键词：
1 year old Adolescent Affect Age Animal Testing Animals Behavioral Biochemical Blood Cells Bone Marrow Breeding Cells Clinical Data Databases Disease Disease Progression Female Fibroblasts Funding Genetic Genetic Status Globoid cell leukodystrophy Goals Grant Infant Inherited Knowledge Live Birth Macaca Macaca mulatta Mesenchymal Stem Cells Modeling Molecular Monoclonal Antibody R24 Mononuclear National Center for Research Resources Pathogenesis Pathologic Peer Group Phase Pregnancy Primates Principal Investigator Process Research Research Infrastructure Research Personnel Resources Running SIV Simian T-lymphotropic virus 1 Skin Source Test Result Testing Tissue Banking Tissue Banks Tissue Sample United States National Institutes of Health Viral Virus base body system cell bank cost genetic pedigree improved male nonhuman primate offspring programs social group success

项目摘要

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 long-term goal of this proposal is to expand and study our colony of nonhuman primates affected with Globoid Cell Leukodystrophy (GLD; Krabbe's disease). This colony of rhesus monkeys represents the only colony of nonhuman primates in the world in which an inherited lysosomal disorder has been recognized, propagated, and is available for study. The primary focus of this R24 grant is to markedly improving the efficiency of producing macaques affected with GLD through a stringent natural breeding program. There are 13 established harem breeding groups containing a carrier male and a combination of carrier and normal females. These social groups have been created based on pedigree data from the carrier colony as well as the availability of normal females who could be placed with carrier males. Of the 21 known pregnancies, there were 21 live births (2 affected, 10 carrier, 8 normal, 1 genetic status to be determined [either normal or carrier]). We continue to characterize disease pathogenesis and generate a database with the affected animals through molecular, biochemical, clinical, behavioral, and pathologic analyses to develop an extensive baseline of knowledge of disease progression in the nonhuman primate model. The 2009 affected infants died at 160 days and 242 days. As an effective alternative to whole animal studies, we have initiated a cell and tissue banking program for the GLD animals. The primary goal for this program is to make viable cells (peripheral blood and bone marrow mononuclear cells, mesenchymal stem cells, and skin fibroblasts) and tissue samples (primary organ systems) available to investigators for their research. As of February 2010, there are 75 total animals in the colony, 48 heterozygous (carrier) animals: 30 breeding age animals (16 males and 14 females), 5 juveniles (4 males and 1 female), and 13 infants/yearlings (7 males, 6 females). Currently the Krabbe Breeding Colony is a conventional colony (i.e., animals are positive for B virus and/or STLV-1). As TNPRC has made it a priority to phase out conventional colonies, plans have been made to derive Krabbe carriers and convert this special colony to one with animals that are negative for the four target viruses (B virus, STLV-1, SIV, SRV). TNPRC has had great success in establishing three different SPF colonies; therefore, the SPF Krabbe colony will be established using the same paradigm. Briefly, carrier offspring between 8-months to 1-year of age will be removed from their conventional natal group and placed in small runs or corncribs with other animals being similarly derived. They will spend the next 2 years in small peer groups and be viral tested 4x/year. After the first 2 years of testing is completed, carrier x carrier and carrier x normal breeding groups will be established with viral testing occurring 2x/year. If an animal tests B+ or STLV+, it will be returned to its natal group or placed with other animals with similar testing results. Because of their genetic value as carriers, they will be maintained for breeding with animals having similar test results. As of April 2010, six carrier infants have entered the process.

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。该提案的长期目标是扩大和研究受球状细胞脑白质营养不良（GLD；克拉伯氏病）影响的非人类灵长类动物群体。这个恒河猴群落代表了世界上唯一一个遗传性溶酶体疾病已被识别、传播并可用于研究的非人类灵长类群落。这项 R24 拨款的主要重点是通过严格的自然育种计划显着提高受 GLD 影响的猕猴的生产效率。已建立13个后宫繁殖群体，其中包括雄性携带者以及携带者和正常雌性的组合。这些社会群体是根据携带者群体的谱系数据以及可以与携带者雄性安置在一起的正常雌性的可用性而创建的。在 21 例已知妊娠中，有 21 例活产（2 例受影响，10 例携带者，8 例正常，1 例遗传状态待确定[正常或携带者]）。我们继续通过分子、生化、临床、行为和病理分析来表征疾病发病机制，并生成受影响动物的数据库，以开发非人类灵长类动物模型中疾病进展的广泛知识基线。 2009年受影响的婴儿分别在160天和242天时死亡。作为整体动物研究的有效替代方案，我们启动了 GLD 动物的细胞和组织库计划。该计划的主要目标是为研究人员提供活细胞（外周血和骨髓单核细胞、间充质干细胞和皮肤成纤维细胞）和组织样本（主要器官系统）。截至 2010 年 2 月，该群体共有 75 只动物，48 只杂合（携带者）动物：30 只繁殖年龄动物（16 只雄性和 14 只雌性）、5 只幼年动物（4 只雄性和 1 只雌性）和 13 只婴儿/一岁动物（7 只）。男性 6 名，女性 6 名）。目前，Krabbe 繁殖群是一个常规群（即动物 B 病毒和/或 STLV-1 呈阳性）。由于 TNPRC 已将逐步淘汰传统群体作为优先事项，因此已制定计划衍生 Krabbe 携带者，并将这一特殊群体转变为对四种目标病毒（B 病毒、STLV-1、SIV、SRV）呈阴性的动物的群体。。 TNPRC 在建立三个不同的 SPF 菌落方面取得了巨大成功；因此，SPF Krabbe 群体将使用相同的范式建立。简而言之，8个月到1岁之间的携带者后代将从其常规出生群体中移出，并与其他类似衍生的动物一起放入小圈或玉米笼中。在接下来的两年里，他们将在小组中度过，并每年接受 4 次病毒测试。前 2 年测试完成后，将建立携带者 x 携带者和携带者 x 正常繁殖群体，每年进行 2 次病毒检测。如果动物测试为 B+ 或 STLV+，它将被送回其出生组或与其他具有类似测试结果的动物放在一起。由于它们作为载体的遗传价值，它们将被保留用于与具有相似测试结果的动物进行繁殖。截至2010年4月，已有6名携带者婴儿进入该程序。