The Maternal/Fetal Interaction

描述（由申请人提供）：我们已经开发了一种具有tata结合蛋白（TBP）靶向突变的小鼠系，该突变将内源性基因替换为相同的版本，只是它产生的蛋白质缺少该蛋白质前135个氨基酸中的111个。这种突变（tbp ^N/^N）纯合的成年小鼠是正常的；然而，突变的胎儿在免疫介导的妊娠中期流产的发生率非常高。我们可以通过多种方式拯救突变体，包括：1)为它们提供野生型的额外胚胎组织；2)在严重免疫受损的水坝中饲养；或3)破坏胎盘中胎儿（2m）的表达。因此，这些小鼠为研究母胎免疫相互作用的母体和胎儿提供了重要的模型系统。我们假设母体/胎儿免疫相互作用涉及母体免疫细胞与胎盘中母体/胎儿界面表达的胎儿基因之间的相互作用；在这种相互作用中，母体或胎儿参与者的改变都可能影响妊娠结局。在这项研究中，我们提出了三个具体目标：目标1，确定母体免疫系统中参与tbp^N/^N胎儿排斥反应的细胞成分；目的2，表征tbp+/+、tbp^N/+和tbp^N/^N胎儿着床部位MHC-I家族基因的表达；和Aim 3，鉴定与胎盘TBP n端相互作用的蛋白。在特异性目的1下获得的结果应揭示可能危及妊娠的母体因素。在Specific Aim 2下获得的结果有望揭示可能危及妊娠的胎儿基因表达缺陷。目标1和目标2下的发现可能会带来对抗慢性流产的新治疗策略。最后，在Specific Aim 3下获得的结果有望揭示可能危及妊娠的表达缺陷背后的基因调控机制。这些结果可能导致预测自然流产易感性的新预后工具。

DESCRIPTION (provided by applicant): We have developed a line of mice bearing a targeted mutation in the TATA-binding protein (TBP) that replaces the endogenous gene with a version that is identical except it produces a protein lacking 111 of the first 135 amino acids of the protein. Adult mice homozygous for this mutation (tbp ^N/^N are normal; however mutant fetuses suffer a very high rate of immune-mediated mid gestational miscarriages. We can rescue the mutants past this crisis in various ways, including: 1) providing them with wildtype extra embryonic tissues; 2) rearing them in severely immune compromised dams; or 3) disrupting fetal (2m expression in their placentas. Thus, these mice provide an important model system for studying both the fetal and the maternal side of the maternal/fetal immune interaction. We hypothesize that the maternal/fetal immune interaction involves the interplay between maternal immune cells and fetal genes expressed at the maternal/fetal interface in the placenta; alteration of either maternal or fetal players in this interaction can affect the outcome of pregnancy. In this study, we propose three Specific Aims: Aim 1, identify the cellular components of the maternal immune system that participate in rejection of tbp^N/^N fetuses; Aim 2, characterize expression of MHC-I family genes at the implantation sites of tbp+/+, tbp^N/+, and tbp^N/^N fetuses; and Aim 3, identify proteins that interact with the TBP N-terminus in placenta. Results obtained under Specific Aim 1 should reveal maternal factors that can compromise pregnancy. Results obtained under Specific Aim 2 are expected to reveal fetal gene expression defects that might compromise pregnancy. Discoveries made under Aims 1 and 2 could lead to novel therapeutic strategies for combating chronic miscarriages. Finally, results obtained under Specific Aim 3 are expected to reveal gene regulatory mechanisms that underlie expression defects which can compromise pregnancy. These results could lead to novel prognostic tools for predicting susceptibility to spontaneous miscarriages.