PILOT PROJECT ON GENETIC DISEASES IN NON-HUMAN PRIMATES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一个试验项目，用来验证一个假设，即在这个国家繁殖的封闭种群中，灵长类动物的高失败率和早逝，部分原因是隐性遗传代谢疾病。由于在相对较小的封闭群体中存在强制性的近亲繁殖，并且创始动物在中间代谢和其他细胞和器官功能的数千个步骤中重要的位点上携带大量基因突变的可能性很高，因此这个假设很可能是正确的。在试点项目中，转诊中心为新英格兰地区灵长类动物研究中心和南阿拉巴马大学医学院负责灵长类动物种群的科学家提供咨询，并提供进入该中心经验丰富的代谢实验室的机会，对发育不良和其他代谢疾病迹象的灵长类动物进行代谢筛查。在该项目的初始阶段，测定了与正常年龄相关的尿液和血清氨基酸、有机酸、碳水化合物和糖胺聚糖水平的标准。这一阶段已经完成。下一阶段将扩展到ncrr支持的灵长类动物群体，出现代谢性疾病迹象的动物，包括无法解释的发育不良、畸形、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一步研究，以确定潜在遗传缺陷的性质。将进一步研究为疾病发病机制和治疗提供新的重要生物医学研究模型的疾病，转诊中心将协助负责这些群体的科学家建立载体动物的育种系。自这项初步研究开始以来，我们收到了下列物种猴子的尿液样本：恒河猴（80只）、狨猴（8只）、松鼠猴（3个亚种）（42只玻利维亚猴、18只秘鲁猴、12只瓜地那猴）。合作机构选择这些动物作为健康对照。对样品进行了研究，以确定半定量分布的氨基酸，有机酸和碳水化合物使用纸色谱方法是便宜的，并已被证明是相当有效的检测异常代谢物在狗和猫的尿液。此外，还对15个样品进行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。两种灵长类动物尿液中的支链氨基酸浓度似乎低于人类尿液中的支链氨基酸浓度。我们现在有了一个基线研究集，它应该为有代谢疾病临床症状的动物研究提供基础。

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.