Genetics of Decidualization

描述（由申请人提供）：在女性生殖道内成功的胚胎发育需要产生一个特殊的母体结构，蜕膜。蜕膜细胞是经过改造的子宫内膜间质细胞。在怀孕期间，蜕细胞位于将入侵的滋养细胞与母体环境分离的界面上。它们保护并促进营养物质流向胚胎。这些蜕细胞的任务是通过调节母体子宫血管发育、免疫和代谢来完成的。妊娠依赖于蜕细胞获得这些特殊功能。调节妊娠建立的机制尚不清楚，我们也不了解与早期妊娠丢失相关的疾病的分子病因学。子宫适应妊娠的协调中断是妊娠失败的潜在原因。我们建议利用一种独特的遗传策略，“染色体替代”，来发现对怀孕的建立至关重要的基因，更具体地说，是对去个体化过程至关重要的基因。我们的分析是基于Dahl SS （DSS）和Fawn HH （FHH）菌株妊娠表现的遗传差异，这两种菌株表现出“正常”的健壮妊娠表现，而Brown Norway （BN）菌株则表现出高妊娠失败率。在第一个特定的目的，脱个体化表型的染色体取代（经济）菌株的大鼠将进行评估。脱个体化表型将在具有单个BN染色体渗入DSS或FHH遗传背景的经济菌株中确定。在第二个具体目标中，分析将集中在18号染色体上，它被认为是影响去个体化的基因的位置。我们计划的实验包括形态学、生理学、生物化学和分子生物学方法。拟议的研究应导致有效的策略，以确定对建立妊娠至关重要的基因和与导致妊娠早期失败的疾病有关的基因。

DESCRIPTION (provided by applicant): Successful embryonic development within the female reproductive tract requires the generation of a specialized maternal structure, the decidua. Decidual cells are modified uterine endometrial stromal cells. During gestation, decidual cells are located at the interface separating invading trophoblast cells from the maternal environment. They protect and facilitate the flow of nutrients to the embryo. These decidual cell tasks are accomplished via modulation of maternal uterine vascular development, immunology, and metabolism. Pregnancy is dependent upon decidual cell acquisition of these specialized functions. Mechanisms regulating the establishment of pregnancy are not well understood, nor do we understand the molecular etiology of diseases associated with early pregnancy loss. Disruptions in the coordination of uterine adaptations to pregnancy are potential causes of gestational failure. We propose to utilize a unique genetic strategy, 'chromosome substitution', to discover genes pivotal to the establishment of pregnancy and more specifically to the process of decidualization. Our analyses are based on genetic differences in pregnancy performance in Dahl SS (DSS) and Fawn HH (FHH) strains, which exhibit 'normal' robust pregnancy performance versus the Brown Norway (BN) strain, which exhibits a high incidence of pregnancy failure. In the first specific aim, decidualization phenotypes of chromosome-substituted (consomic) strains of rats will be assessed. Decidualization phenotypes will be determined in consomic strains possessing individual BN chromosomes introgressed into either the DSS or the FHH genetic backgrounds. In the second specific aim, the analysis will focus on Chromosome 18, which has been implicated as the location of genes impacting decidualization. Our planned experimentation includes morphological, physiological, biochemical, and molecular biology approaches. The proposed research should lead to effective strategies for identifying genes critical for the establishment of pregnancy and genes implicated in diseases leading to early pregnancy failure. PUBLIC HEALTH RELEVANCE: Early pregnancy failure is a significant health problem. The appropriate development and functioning of decidual cells is essential for the establishment and maintenance of pregnancy. Elucidation of the genetics of decidual cell development is a key to understanding the etiology of early pregnancy failure.