The Maternal/Fetal Interaction

描述（由申请人提供）：我们开发了一系列小鼠，这些小鼠在TATA结合蛋白（TBP）中携带靶向突变，该突变用相同的版本取代了内源基因，只是它产生的蛋白质缺乏前135个氨基酸中的111个。该蛋白质的氨基酸。对于这种突变纯合子的成年小鼠（tbp ^N/^N）是正常的;然而，突变的胎儿遭受非常高的免疫介导的中期妊娠流产率。我们可以通过各种方式拯救突变体度过这一危机，包括：1）为它们提供野生型额外的胚胎组织; 2）将它们饲养在严重免疫受损的母鼠中;或3）破坏胎盘中的胎儿β 2 m表达。因此，这些小鼠为研究母体/胎儿免疫相互作用的胎儿和母体侧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和胎盘中母体/胎儿界面表达的胎儿基因之间的相互作用;这种相互作用中母体或胎儿参与者的改变可能影响妊娠结局。在这项研究中，我们提出了三个具体的目标：目标1，确定参与tbp^N/^N胎儿排斥的母体免疫系统的细胞成分;目标2，表征tbp+/+，tbp^N/+和tbp^N/^N胎儿植入部位的MHC-I家族基因的表达;目标3，确定与胎盘中TBP N-末端相互作用的蛋白质。根据具体目标1获得的结果应揭示可能影响妊娠的母体因素。根据特定目标2获得的结果预计将揭示可能危及妊娠的胎儿基因表达缺陷。根据目标1和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妊娠的表达缺陷的基因调控机制。这些结果可能会导致新的预测工具，预测自然流产的易感性。

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.