Genetics of Decidualization

描述（由申请人提供）：在雌性生殖道内成功的胚胎发育需要产生专门的母体结构，即蜕膜。蜕膜细胞是修饰的子宫内膜间质细胞。在妊娠期间，蜕膜细胞位于将侵入的滋养层细胞与母体环境分开的界面。它们保护和促进营养物质流向胚胎。这些蜕膜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。妊娠依赖于蜕膜细胞获得这些特殊功能。调节妊娠建立的机制还不清楚，我们也不了解与早期妊娠丢失相关的疾病的分子病因。子宫对妊娠的适应性协调失调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”，发现关键的基因建立怀孕，更具体地说，蜕膜化的过程。我们的分析是基于Dahl SS（DSS）和Fawn HH（FHH）品系妊娠性能的遗传差异，这两种品系表现出“正常”的稳健妊娠性能，而Brown Norway（BN）品系表现出较高的妊娠失败率。在第一个具体目标中，将评估大鼠染色体取代（染色体组）品系的蜕膜化表型。将在具有渗入DSS或FHH遗传背景的单个BN染色体的consomic菌株中确定蜕膜化表型。在第二个具体目标中，分析将集中在18号染色体上，该染色体被认为是影响蜕膜化的基因的位置。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战略，以确定基因的关键建立怀孕和基因牵连的疾病导致早孕失败。 公共卫生相关性：早孕失败是一个严重的健康问题。蜕膜细胞的适当发育和功能对于妊娠的建立和维持至关重要。阐明蜕膜细胞发育的遗传学是了解早期妊娠失败病因的关键。

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.