Mouse Models of Vitamin Transport Defects

描述（由申请人提供）： SLC 19 A3是维生素转运蛋白家族的成员，该家族包括还原叶酸载体SLC 19 A1和高亲和力硫胺素转运蛋白SLC 19 A2。该溶质载体亚家族的成员是12跨膜蛋白，其特异性转运微量营养素，如叶酸（SLC 19 A1）或硫胺素（SLC 19 A2和SLC 19 A3）。我们假设SLC 19 A3作为硫胺素进入体内的主要门户发挥作用，作为主要的（如果不是唯一的）胎盘硫胺素转运蛋白发挥作用。它也可能是一种主要的肠道硫胺素转运蛋白。硫胺素和其他维生素一样，是通过饮食摄入获得的。全身性（饮食）硫胺素缺乏可导致多种问题，包括神经退行性变、消瘦和死亡。本研究旨在描述SLCI 9A 3 RNA和蛋白在发育中的胚胎和成体组织中的表达模式。通过SLC 19 A3将硫胺素递送到组织中的功能作用将使用具有SLC 19 A3的靶向缺失的小鼠模型来解决。此外，将创建其中仅在某些组织中缺失SLC 19 A3的转基因小鼠品系，以评估硫胺素对特定发育阶段和个体器官系统的重要性。这些研究将提供有关硫胺素在发育和正常及疾病系统中的作用的重要信息。 建议的工作将在Ellis Neufeld博士的实验室和儿童医院血液科提供的出色环境中进行。Neufeld博士在遗传学、血液学和生物化学方面的专业知识，以及与小鼠发育和转基因模型专家（如Stuart Orkin博士和Nancy Andrews博士）的密切联系，将对申请人进一步发展独立的学术研究事业产生巨大影响。拟议的项目将在一流的培训环境中进行，这将提高申请人的技能和知识储备。使用转基因/基因敲除方法提出的实验类型可能会为申请人提供几种新的研究途径，以便在未来作为独立研究人员进行重点研究，并且肯定会提供必要的初步数据，以争取完全独立的资金。

DESCRIPTION (provided by applicant): SLC19A3 is a member of the vitamin transporter family that includes the reduced folate carrier, SLC 19A1 and the high-affinity thiamine transporter, SLC19A2. Members of this solute carrier sub-family are 12-membrane spanning proteins that specifically transport micronutrients such as folate (SLC19A1) or thiamine (SLC19A2 and SLC19A3). We hypothesize that SLC19A3 functions as a major portal for thiamine into the body, functioning as a major (if not the only) placental thiamine transporter. It is likely to also be a major intestinal thiamine transporter as well. Thiamine, like other vitamins, is obtained through dietary intake. Systemic (dietary) thiamine deficiency can lead to a multitude of problems including neurodegeneration, wasting, and death. This study proposes to characterize the expression pattern of SLCI9A3 RNA and protein in developing embryos and adult tissues. The functional role of thiamine delivery into tissues via SLC19A3 will be addressed using a mouse model with a targeted deletion of SLC19A3. Additionally, transgenic mouse lines in which SLC19A3 is deleted in only certain tissues will be created in order to assess the importance of thiamine to particular stages of development and to individual organ systems. These studies will provide important information concerning the contribution of thiamine in development and in normal and disease systems. The work proposed will be performed in the outstanding environment provided by Dr. Ellis Neufeld's laboratory and the Division of Hematology at Children's Hospital. Dr. Neufeld's expertise in genetics, hematology and biochemistry, as well as the close proximity of experts in mouse development and transgenic models (e.g. Drs. Stuart Orkin and Nancy Andrews) will have a great impact on the further development of the applicant towards an independent academic research career. The proposed project will be carried out in a superb training environment that will enhance the applicant's skill and knowledge repertoire. The types of experiments proposed, using a transgenic/knockout approach, will likely provide the applicant with several new research avenues to focus on in the future as an independent researcher, and will certainly provide the necessary preliminary data to compete for completely independent funding.