NONHUMAN PRIMATE MODEL FOR KRABBE'S DISEASE

克拉伯病的非人类灵长类动物模型

• 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
• 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

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.

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， 包括其它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。 这项提案的长期目标是扩大和研究我们的群体的非人灵长类动物受影响的球状细胞脑白质营养不良（GLD;克拉伯病）。这个猕猴群体代表了世界上唯一一个非人灵长类群体，其中遗传性溶酶体疾病已被确认，繁殖，并可用于研究。 这项R24补助金的主要重点是通过严格的自然繁殖计划显着提高生产受GLD影响的猕猴的效率。 有13个已建立的后宫繁殖组，包括一个携带者男性和携带者和正常女性的组合。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男性一起放置的正常女性的可用性创建的。 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例遗传状态待定[正常或携带者]）。我们继续描述疾病的发病机制，并通过分子、生化、临床、行为和病理分析生成受影响动物的数据库，以在非人灵长类动物模型中建立广泛的疾病进展知识基线。 2009年受影响的婴儿分别在160天和242天死亡。 作为整个动物研究的有效替代方案，我们已经启动了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，殖民地中共有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只幼龄动物（4只雄性和1只雌性）和13只幼仔/一岁幼畜（7只雄性，6只雌性）。 目前，克拉布繁殖群是一个传统的殖民地（即，动物对B病毒和/或STLV-1呈阳性）。 由于TNPRC已将逐步淘汰传统菌落作为优先事项，因此已制定计划，以获得克拉布病毒携带者，并将这一特殊菌落转变为对四种目标病毒（B病毒、STLV-1、SIV、SRV）呈阴性的动物。 TNPRC在建立三个不同SPF菌落方面取得了巨大成功;因此，将使用相同的范例建立SPF Krabbe菌落。 简而言之，将8个月至1岁的携带者后代从其常规纳塔尔组中取出，并与其他类似来源的动物一起放置在小型饲养场或玉米笼中。 他们将在接下来的2年里在小的同龄人群体中度过，并每年进行4次病毒测试。 在前2年的检测完成后，将建立携带者x携带者和携带者x正常繁殖组，病毒检测每年进行2次。 如果动物检测结果为B+或STLV+，则将其送回其纳塔尔组或与具有相似检测结果的其他动物一起放置。 由于它们作为携带者的遗传价值，将保留它们与具有相似试验结果的动物进行育种。 截至2010年4月，已有6名携带者婴儿进入这一进程。