NONHUMAN PRIMATE MODEL FOR KRABBE'S DISEASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这项提议的长期目标是扩大和研究我们的非人类灵长类动物群体，这些灵长类动物患有球状细胞白血病营养不良症(GLD；Krabbe病)。这群恒河猴代表了世界上唯一一群非人类灵长类动物，在其中遗传性溶酶体疾病已被识别、繁殖并可用于研究。这笔R24赠款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。已建立的后宫繁育群有13个，包括一个携带者雄性和一个携带者和正常雌性的组合。这些社会群体是基于携带者群体的血统数据以及可以与携带者男性配对的正常雌性的可用性而创建的。在已知的21例妊娠中，有21例活产(2例感染，10例携带者，8例正常，1例基因状态有待确定[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，与受影响的动物建立数据库，以建立非人类灵长类动物模型中疾病进展的广泛基线知识。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，我们为GLD动物启动了一个细胞和组织库计划。该计划的主要目标是使活细胞(外周血和骨髓单个核细胞、间充质干细胞和皮肤成纤维细胞)和组织样本(初级器官系统)可供研究人员使用。截至2010年2月，该种群共有75只动物，48只杂合子(携带者)动物：30只处于繁殖年龄的动物(16只雄性和14只雌性)，5只幼崽(4只雄性和1只雌性)，以及13只婴儿/一岁幼崽(7只雄性，6只雌性)。 目前，Krabbe繁育群体是一个常规群体(即动物对B病毒和/或STLV-1呈阳性)。由于TNPRC已将逐步淘汰常规群体作为优先事项，已制定计划，以衍生Krabbe携带者，并将这个特殊群体转变为具有四种目标病毒(B病毒、STLV-1、SIV、SRV)阴性动物的群体。TNPRC已经成功地建立了三个不同的SPF菌落；因此，SPF Krabbe菌落将使用相同的范式建立。简而言之，8个月到1岁的携带者后代将被从他们的传统出生群体中移除，并与类似的其他动物一起被放在小笼子或玉米床中。在接下来的两年里，他们将在小团体中度过，并每年接受4次病毒检测。在头两年检测完成后，将建立携带者x携带者和携带者x正常繁育小组，每年进行2x次病毒检测。如果一只动物检测到B型或STLV病毒，它将被送回其出生组或与其他检测结果相似的动物放在一起。由于它们作为携带者的遗传价值，它们将被保留下来，以便与具有类似测试结果的动物进行繁殖。截至2010年4月，已有6名携带者婴儿进入这一过程。

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.