The Maternal/Fetal Interaction

描述(申请人提供)：我们已经开发出一种在TATA结合蛋白(TBP)中带有靶向突变的小鼠，该突变用一个相同的版本取代内源基因，除了它产生的蛋白质缺少该蛋白质的前135个氨基酸中的111个氨基酸。这种突变(tBP^N/^N)纯合的成年小鼠是正常的；然而，突变的胎儿遭受非常高的免疫介导的妊娠中期流产率。我们可以通过各种方式拯救突变人度过这场危机，包括：1)为他们提供野生型额外的胚胎组织；2)在严重免疫受损的水坝中饲养他们；或3)扰乱胎儿(2M)在胎盘中的表达。因此，这些小鼠为研究母体和胎儿免疫相互作用的胎儿和母体侧提供了一个重要的模型系统。我们假设母胎免疫相互作用涉及母体免疫细胞和胎盘母胎界面表达的胎儿基因之间的相互作用；在这种相互作用中，母体或胎儿角色的改变可能会影响妊娠结局。在这项研究中，我们提出了三个具体的目标：目的1，确定参与TBP^N/^N胎儿排斥反应的母体免疫系统的细胞成分；目的2，研究MHC-I家族基因在TBP+/+，TBP^N/+和TBP^N/^N胚胎着床点的表达；目的3，确定胎盘中与TBP N末端相互作用的蛋白质。在特定目标1下获得的结果应揭示可能危及妊娠的母体因素。在特定目标2下获得的结果有望揭示可能危及怀孕的胎儿基因表达缺陷。根据目标1和目标2所做的发现可能会导致对抗慢性流产的新的治疗策略。最后，在特定目标3下获得的结果有望揭示可能危及怀孕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的预后工具。

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.