IRON AND COPPER IN HEALTH AND DISEASE

候选人是医学博士和博士，接受过哺乳动物遗传学方面的培训，在简·吉齐尔的实验室从事博士后工作，同时在加州大学旧金山分校接受临床分子遗传学研究员培训。加州大学旧金山分校是一个极好的研究环境，为候选人提供了各种科学资源。他的长期研究目标是建立一个专注于哺乳动物金属代谢的独立研究实验室。他的临床目标是遗传病的分子诊断领域。他的长期目标是建立一个致力于诊断这些罕见疾病的临床分子遗传学实验室。用遗传学方法鉴定与金属代谢有关的哺乳动物基因和确定相应蛋白质的特性将是这一提议的主要重点。这项研究的目的有两个：1)通过定位克隆SLA(性连锁贫血)中受影响的基因来确定肠道铁输出物。SLA是一种铁输出缺陷的小鼠突变体，它提供了识别铁通过肠道转运过程中的关键成分的方法，这一过程知之甚少。利用种间杂交、祖先染色体定位、排异定位等方法对SLA基因进行精确定位，构建SLA区域物理图谱。在转基因小鼠中，SLA缺陷与大插入克隆的功能互补将被用于进一步提炼SLA区域。候选基因将通过标准方法识别，并评估其在SLA中的作用。2)鉴定在脑中表达的新的铜蓝蛋白同源物，并确定其在铁和铜代谢中的作用。将对完整的cdna进行鉴定和测序，并确定基因的染色体位置。研究其时空表达模式和同源基因敲除有助于确定其功能。

The candidate is a MD., Ph.D. with training in mammalian genetics pursuing post-doctoral work in the laboratory of Jane Gitschier concurrent with training at UCSF as a Clinical Molecular Genetics Fellow. UCSF is an excellent research environment with diverse scientific resources available to the candidate. His long term research goals are to establish an independent research laboratory focused on mammalian metal metabolism. His clinical goals are in the field of molecular diagnostics of genetic diseases. His long term goal is to establish a clinical molecular genetics laboratory devoted to the diagnosis of these rare disorders. Genetic approaches to the identification of mammalian genes involved in metal metabolism and characterization of the corresponding proteins will be the primary focus of this proposal. There are two specific aims in this research proposal: 1) Identify the intestinal iron exporter by positional cloning of the gene affected in sla (sex linked anemia). Sla, a mouse mutant with defective iron export, provides the means to identify a key component in the poorly understood process of iron transit through the intestine. The location of sla gene will be refined with an inter-specific cross, ancestral chromosome mapping, and exclusion mapping and a physical map of sla region will be constructed. Functional complementation of the sla defect with large insert clones in transgenic mice will be used to further refine the sla region. Candidate genes will be identified by standard means and evaluated for a role in sla. 2) Characterize a novel ceruloplasmin homologue expressed in the brain and determine its role in iron and copper metabolism. The complete cDNA will identified and sequenced and the chromosomal location of the gene determined. Study of temporal and spatial mRNA expression pattern and a homologous knockout will help define its functional role.