The Maternal/Fetal Interaction

母体/胎儿的相互作用

• 批准号: 7347047
• 负责人: EDWARD E SCHMIDT
• 金额: $ 32.4万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7347047
• 关键词: Adult; Affect; Amino Acids; Biological Models; Cell Nucleus; Cells; Chronic; Common iliac lymph node; Communication; DNA-Directed RNA Polymerase; Defect; Exhibits; Family; Fetus; Gene Expression; Gene Family; Genes; Genetic Transcription; Immune; Immune system; Lead; Maternal-Fetal Exchange; Mediating; Methods; Mothers; Mus; Mutation; Placenta; Predisposition; Pregnancy; Pregnancy Outcome; Proteins; Rag1 Mouse; Rate; Regulator Genes; Role; Side; Signal Transduction; Site; Spontaneous abortion; Standards of Weights and Measures; TATA-Box Binding Protein; Testing; Tissues; embryo tissue; fetal; fetus cell; implantation; mutant; new technology; novel; novel therapeutics; prognostic; tool

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.

描述（由申请人提供）：我们开发了一系列 TATA 结合蛋白（TBP）带有靶向突变的小鼠，该突变用相同的版本替换内源基因，只是产生的蛋白质缺乏该蛋白质前 135 个氨基酸中的 111 个。这种突变纯合的成年小鼠（tbp ^N/^N 是正常的；然而突变的胎儿遭受免疫介导的妊娠中期流产的几率非常高。我们可以通过多种方式拯救突变体度过这场危机，包括： 1）为它们提供野生型胚胎外组织； 2）在免疫严重受损的水坝中饲养它们；或3）破坏胎儿（胎盘中的2m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方面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以影响母体/胎儿免疫相互作用。 怀孕的结果。在本研究中，我们提出了三个具体目标： 目标 1，识别参与 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 胎儿着床位点的 MHC-I 家族基因表达；目标 3，识别与 TBP N 末端位于胎盘中。具体目标 1 下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。目标 1 和 2 下的发现可能会带来对抗慢性流产的新治疗策略。最后，特定目标 3 下获得的结果有望揭示表达背后的基因调控机制 可能会影响怀孕的缺陷。这些结果可能会带来新的预后工具来预测自然流产的易感性。