Regulation of Leukemia Inhibitory Factor (LIF) for early embryo implantation

简介（由申请人提供）：西尔维娅·拉莫斯是一名医学博士，拥有丰富的临床经验，包括内科、自身免疫性疾病以及生殖生物学和临床胚胎学基础科学。她致力于不明原因不孕症的研究。Silvia的长期职业目标是成为一名独立的受资助的科学家，从事生殖生物学和RNA代谢的基础研究，并以有意义的目标转化为解释人类不孕症的原因。Silvia的短期职业目标是1)获得更具体和深入的RNA代谢知识；2)掌握使用siRNA或shRNA敲除特定蛋白的技术；3)生成基因工程小鼠，在体内对模型进行测试；4)在负责任的研究行为方面获得额外的培训；5)发展写作技巧、资助、初步数据和出版物，使自己成为R01的PI，并使自己成为生殖和RNA领域的全国领导者。建议的研究计划，职业发展活动，指导团队和机构环境都是唯一适合帮助申请人实现这些目标。本项目的目的是研究一种特定的植入因子，白血病抑制因子（LIF）的调控。生活

DESCRIPTION (provided by applicant): Silvia Ramos is an MD PhD with a diverse portfolio including a strong clinical formation in internal medicine, autoimmune disease as well as a solid training in basic science of reproductive biology and clinical embryology. She is committed to devoting herself to the study of infertility of unexplained basis. Silvia's long-term-career goal i to be an independent funded scientist, doing basic research on reproductive biology and RNA metabolism with a meaningful goal to translate into providing explanations of human infertility of unexplained basis. Silvia's short-term career goals are to 1) gain a more specific and in depth knowledge on RNA metabolism; 2) master the techniques of knocking down specific proteins either using siRNA or shRNA; 3) generate a genetic engineered mouse to test the model in vivo; 4) obtain additional training in responsible conduct of research; and 5) develop writing skills, grantsmanship, preliminary data and publications to be credible as the PI of an R01 and establish herself as a national leader in the reproductive and RNA field. The proposed research plan, career development activities, mentorship team, and institutional environment are all uniquely suited to assist the applicant in achieving these goals. The goal of this project is to investigate the regulation of a specific implantation factor, Leukemia Inhibitory Factor (LIF). LIF is required for successful embryonic implantation to the uterus in mice. Our hypothesis is that Leukemia Inhibitory Factor (LIF) is regulated at the post-transcriptional level. In aim 1, the PI wll selectively overexpress and down-regulate each of the ZFP36 proteins (TTP, ZFP36L1 and ZFP36L2) in human cell lines to determine whether LIF mRNA can be destabilized by these proteins. In Aim 2, the PI will identify and characterize which sequences of LIF mRNA are involved in binding to ZFP36 proteins. In Aim 3, the PI will test the biological relevance of LIF mRNA destabilization by ZFP36 proteins during the implantation by creating a mouse model expressing higher than normal levels of one ZFP36 protein in uterine epithelial cells. The expected outcome of this proposal is an improved knowledge of the mechanisms by which a specific implantation factor, LIF, is regulated; and how this regulation influences the process of early embryo implantation. To support Dr. Ramos's career development, she will pursue coursework in basic advanced molecular biology, modeling human disease in mice, and research ethics. The mentorship team, which includes internationally-recognized, independently-funded investigators with expertise in gene regulation and RNA metabolism (Marzluff); and generation of genetically engineered mice of human disease and biology of implantation (Caron), will guide Dr. Ramos's research and career development. The research environment will provide a productive, collegial, and collaborative atmosphere ideal for pursuing the above research and training goals. PUBLIC HEALTH RELEVANCE: Female infertility is a worldwide problem affecting 10% of the 1.5 billion women at reproductive age. In US this corresponds to 2.1 million married women ages 15-44 who are infertile-for whom the cause of infertility remains unknown for 15%. During the past two decades there has been a consistent trend towards delayed childbearing in most developed countries, increasing age-related infertility. In the US, 7.3 million women ages 15-44 have used infertility services. The relative inefficiency of implantation in humans remains, to a great extent, inexplicable. The goal of this and subsequent research is to investigate the post-transcriptional regulation of the Leukemia Inhibitory Factor (LIF) and its effect on implantation i vivo. New generated information may, consequently, bring novel treatment options for female infertility of unexplained basis.