PILOT PROJECT ON GENETIC DISEASES IN NON-HUMAN PRIMATES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这是一个试验性项目，旨在检验这样一种假设，即在这个国家繁育的封闭群体中，灵长类动物无法茁壮成长和过早死亡的频率很高，部分原因是隐性遗传的代谢性疾病。由于在规模相对较小的封闭群体中存在强制性近亲交配，以及创始动物在中间代谢和其他细胞和器官功能的数千步中至关重要的位置上携带大量基因突变的可能性很高，这一假设很可能是正确的。在试点项目中，转介中心为新英格兰地区灵长类研究中心和南阿拉巴马大学医学院负责灵长类群体的科学家提供咨询，并提供进入该中心经验丰富的代谢实验室的通道，以便对发育迟缓和其他代谢性疾病迹象的灵长类进行代谢筛查。在这个项目的初始阶段，对感兴趣的物种进行了尿液和血清氨基酸、有机酸、碳水化合物和糖胺聚糖水平的正常年龄相关标准的测定。这一阶段已经完成。在下一阶段将扩大到NCRR支持的灵长类动物群体，表现出可能表明代谢性疾病的迹象的动物，包括原因不明的发育迟缓、变形障碍、神经和行为异常、癫痫、呕吐、代谢性酸中毒、生长迟缓、白内障和骨骼畸形，将被筛查尿液和血液中是否存在异常代谢物。有异常的动物将通过适当的生化和分子方法进行进一步研究，以确定潜在遗传缺陷的性质。为疾病发病机制和治疗的生物医学研究提供新的重要模式的疾病将得到进一步研究，转诊中心将协助负责这些群体的科学家建立携带者动物的繁育系。在这项初步研究开始以来的一段时间里，我们收到了以下物种的猴子的尿样：恒河猴(80只)、绒猴(8只)、3个亚种的松鼠猴子(42只玻利维亚猴、18只秘鲁猴、12只瓜亚族猴)。这些动物被合作机构选为健康对照。对样品进行研究，以确定氨基酸、有机酸和碳水化合物的半定量分布，使用纸色谱方法，这些方法成本低廉，已被证明在检测狗和猫尿中的异常代谢物方面相当有效。此外，对15个样品进行了气相色谱和高效液相色谱检测，以验证半定量结果。根据人类和狗的标准，没有发现明显的异常，灵长类物种之间也没有明显的差异。这两种灵长类动物尿液中支链氨基酸的浓度似乎低于人类尿液中的浓度。我们现在有了一个基线研究集，应该为对临床症状提示代谢性疾病的动物进行研究提供基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a pilot project to test the hypothesis that the high frequency of failure to thrive and early death among primates in closed colonies bred in this country is, in part, due to recessively inherited metabolic diseases. Because of the obligatory inbreeding present in closed colonies of relatively small size and the high probability that founding animals carry a number of gene mutations at loci important in the thousands of steps in intermediary metabolism and other cell and organ functions, it is likely that this hypothesis is correct. In the pilot project, the Referral Center provided consultation for scientists in charge of primate colonies at the New England Regional Primate Research Center and the South Alabama University School of Medicine and provided access to the Center's experienced metabolic laboratory for metabolic screening of primates with failure to thrive and other signs of metabolic disease. In the initial phase of this project, normal age related standards for urinary and serum levels of amino acids, organic acids, carbohydrates, and glycosaminoglycans were determined in the species of interest. This phase has been completed. In the next phase to be expanded to an NCRR-supported primate colony, animals exhibiting signs that may be indicative of metabolic disease, including unexplained failure to thrive, dysmorphia, neurologic and behavioral abnormalities, seizures, vomiting, metabolic acidosis, growth retardation, cataracts, and bony deformities, will be screened for the presence of abnormal metabolites in urine and blood. Animals with abnormalities will be further studied by appropriate biochemical and molecular methods to determine the nature of the underlying genetic defect. Disorders that offer new and important models for biomedical research on disease pathogenesis and therapy will be further studied and the Referral Center will assist the scientists in charge of these colonies in establishing breeding lines of carrier animals. During the period since this pilot study began we have received urine samples from monkeys of the species indicated: Rhesus (80), Marmosets (8), Squirrel monkeys of 3 subspecies (42 Bolivian, 18 Peruvian, 12 Guayanese). These animals were chosen by the collaborating institution as healthy controls. Samples were studied to determine semi-quantitative distribution of amino acids, organic acids and carbohydrates using paper chromatographic methods that are cheap and have been shown to be reasonably effective in detecting abnormal metabolites in dog and cat urine. In addition, 15 samples were examined by gas chromatography and HPLC to verify the semi-quantitative findings. No striking abnormalities based on human and dog standards were seen and there were no obvious differences between the primate species. The concentration of branched chain amino acids in the urine of the two primate species studied appears to be lower than that in human urine. We now have a baseline study set that should provide the basis for studies in animals with clinical signs of illness suggestive of metabolic disease.