Center of Excellence in Molecular Hematology

总体描述(由申请人提供)： 我们建议成立一个以金属代谢和血红素生物合成为主题的分子血液学研究中心(CEHM)。CEMH将支持来自犹他大学和其他五所大学多个系的17名NIH支持的调查人员的活动。这些研究人员专注于铁、铜和锌，以及在正常和疾病状态下卟啉和血红素的生物合成。 金属代谢研究强调金属的遗传和生化基础，包括动态平衡的吸收、运输和细胞分布。在酵母、斑马鱼、蠕虫和老鼠模型中研究了感兴趣的基因。模型系统的结果被用来检验临床假说。这些研究因为有遗传性铁超载障碍的大型家系的存在而得到了便利。 关于卟啉和血红素生物合成的研究从卟啉生物合成酶的结构研究延伸到人类卟啉的动物模型。同样，有遗传性卟啉代谢障碍的大型家系也可用于翻译研究。 CEMH将支持四个核心，这将促进对金属和血红素的研究。这些核心包括X射线结晶学、蛋白质纯化和代谢组学。我们预计代谢组学核心中心将成为金属和血红素研究的国家参考中心。CEMH还将支持针对翻译研究和识别影响金属摄取、运输和分配的基因的试点项目。试点项目利用了犹他州在遗传分析、金属生理学和庞大的患者群体方面的优势。

DESCRIPTION, OVERALL (provided by applicant): We propose a Center of Exellence in Molecular Hematology (CEHM) with the theme of metal metabolism and heme biosynthesis. The CEMH will support the activities of 17 NIH-supported investigators from multiple departments at the University of Utah and five other universities. These investigators focus on iron, copper, and zinc and on the biosynthesis of porphyrins and heme in normal and disease states. Research in metal metabolism emphasizes the genetic and biochemical basis of metals, including homeostasis uptake, transport, and cellular distribution. Genes of interest are studied in yeast, zebrafish, worms, and mouse models. Results from model systems are used to test clinical hypotheses. These studies are facilitated by the availability of large pedigrees with inherited iron overload disorders. Research in porphyria and heme biosynthesis extends from structural studies of porphyrin biosynthetic enzymes to animal models of human porphyrins. Again, large pedigrees with inherited disorders of porphyrin metabolism are available for translational studies. The CEMH will support four Cores that will facilitate research on metals and heme. These Cores include X-Ray Crystallography, Protein Purification, and Metabolomics. We expect the Metabolomics Core to be national reference centers for studies on metals and heme. The CEMH will also support pilot projects directed both at translational research and at identification of genes that affect metal uptake transport and distribution. The pilot projects take advantage of Utah's strengths in genetic analysis, metal physiology, and a large accessible patient population.