Mouse Models of Vitamin Transport Defects

描述（由申请人提供）：

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.