PILOT PROJECT ON GENETIC DISEASES IN NON-HUMAN PRIMATES

非人类灵长类动物遗传疾病试点项目

• 批准号: 7391945
• 负责人: URS GIGER
• 金额: $ 0.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391945
• 关键词: PILOT; PROJECT; GENETIC; DISEASES; NON

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这是一个试验项目，以测试一个假设，即在这个国家饲养的封闭群落中，灵长类动物的高频率无法茁壮成长和过早死亡，部分原因是由于遗传性代谢疾病。由于在规模相对较小的封闭群体中存在强制性近亲繁殖，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的重要位点上携带许多基因突变的可能性很高，因此这一假设很可能是正确的。在试点项目中，转介中心为负责新英格兰地区灵长类动物研究中心和南亚拉巴马大学医学院灵长类动物群落的科学家提供咨询，并提供进入该中心经验丰富的代谢实验室的机会，对无法茁壮成长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，在感兴趣的种属中确定了尿和血清中氨基酸、有机酸、碳水化合物和糖胺聚糖水平的正常年龄相关标准。这一阶段已经完成。在扩展至NCRR支持的灵长类动物群体的下一阶段，将筛选表现出可能指示代谢性疾病的体征的动物，包括不明原因的生长迟缓、畸形、神经和行为异常、癫痫发作、呕吐、代谢性酸中毒、生长迟缓、白内障和骨畸形，以确定尿液和血液中是否存在异常代谢物。将通过适当的生物化学和分子方法对异常动物进行进一步研究，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的生物医学研究提供新的重要模型的疾病，转诊中心将协助负责这些菌落的科学家建立携带动物的繁殖系。自本项初步研究开始以来，我们收到了所示种属猴的尿样：恒河猴（80）、绒猴（8）、3个亚种的松鼠猴（42只玻利维亚猴、18只秘鲁猴、12只圭亚那猴）。合作机构选择这些动物作为健康对照。对样品进行了研究，以使用便宜的纸色谱法测定氨基酸、有机酸和碳水化合物的半定量分布，该方法已被证明在检测犬和猫尿液中的异常代谢物方面相当有效。此外，15个样品进行了检查，通过气相色谱法和高效液相色谱法，以验证半定量的结果。根据人和犬的标准，未观察到显著异常，灵长类动物之间也无明显差异。研究的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。我们现在有一个基线研究集，应该为在具有提示代谢疾病的疾病临床体征的动物中进行研究提供基础。