Dissecting gene dysregulation at the maternal-fetal interface in preeclampsia

抽象的。拟议研究的目标是让Alejandra Elder Ontiveros博士获得以下方面的额外培训 生殖生物学博士后她在Escuela de Medicina伊格纳西奥获得医学博士学位 A.桑托斯，蒙特雷技术和研究所。在理查德博士的指导下 贝林格（贝勒医学院），她最近完成了她的博士研究工作子宫 小鼠的发育。然后她转到苏珊·费舍尔博士（加州大学旧金山分校）的实验室， 弗朗西斯科，加州大学旧金山分校），在那里她正在学习人类胎盘生物学和一个强大的组学技术-质量 质谱法（MS）。在本补充条款所附的裁决中，费舍尔集团正在测试 子痫前期胎盘细胞滋养层细胞基因表达谱研究 (PE)患者将导致识别在这种综合征中起重要作用的新分子。的 这一策略的动力是发现PE始终与这些细胞的异常分化相关， 细胞，这转化为浅胎盘和这种综合征的母体迹象。于本 作为R37奖项的一部分，该小组正在使用单细胞测序来揭示疾病相关的改变， 在分化CTB的发展轨迹中。本文提出的实验目标是： 应用是表征从PE患者和对照的胎盘分离的CTB的蛋白质组 女性，同样的细胞正在接受单细胞测序。结果将使添加 对后一项工作有重大意义的新层面。首先，这些数据将把研究结果从mRNA扩展到 蛋白质水平，重要的是考虑到两者之间经常缺乏一致性。第二，免疫定位 两个数据集中差异表达的分子将精确定位受影响的分子的确切位置。 细胞驻留。这些信息将有助于制定未来实验的策略，以测试其有效性。 功能协调发展的为了促进她的职业发展，她将参加课程（例如，MS，生物信息学，统计学，资助 写作，指导和职业发展），并寻求额外的培训经验（例如，负责 开展研究、多样性和外联）。为了磨练她的沟通技巧，她会定期给 在UCSF和国家会议上的演讲。她的研究和职业发展将由一名 具有相关专业知识的高级教师的杰出团队表示：琳达朱迪斯博士（人类子宫 生物学，子宫内膜异位症，不孕症），罗伯特Blelloch博士（癌症生物学和免疫学，小鼠胎盘 Steven Hall博士（质谱分析，包括仪器和数据分析）。都有 杰出的指导和培训记录;两个是医生科学家（博士Giudice和Blelloch）。他们的 对候选人的承诺和她的主要导师费舍尔博士的热情支持，确保了 培训计划的成功以及候选人作为教师的独立职业生涯的最终启动 一家顶级医学研究机构的成员和首席研究员。

Abstract. The goal of the proposed research is for Dr. Alejandra Elder Ontiveros to obtain additional training in reproductive biology at the postdoctoral level. She received her MD degree from Escuela de Medicina Ignacio A. Santos, Instituto Tecnologico y de Estudios Superiores de Monterrey. Under the mentorship of Dr. Richard Behringer (Baylor College of Medicine), she recently completed her doctoral work studying uterine development in mice. Then she moved to the laboratory of Dr. Susan Fisher (University of California San Francisco, UCSF) where she is learning human placental biology and a powerful -omics technology—mass spectrometry (MS). In the award to which this supplement is appended, the Fisher group is testing the hypothesis that global gene expression profiling of cytotrophoblasts (CTBs) from placentas of preeclampsia (PE) patients will lead to the identification of novel molecules that play important roles in this syndrome. The impetus for this strategy is the finding that PE is consistently associated with aberrant differentiation of these cells, which translates into shallow placentation and the maternal signs of this syndrome. During the current segment of this R37 award, the group is using single cell sequencing to reveal disease-associated alterations in the developmental trajectories of differentiating CTBs. The goal of the experiments proposed in this application is to characterize the proteomes of CTBs isolated from the placentas of PE patients and control women, the same cells that are being subjecting to single-cell sequencing. The results will enable the addition of significant new dimensions to the latter work. First, the data will extend the findings from the mRNA to the protein level, important given the frequent lack of concordance between the two. Second, immunolocalization of the differentially expressed molecules in both datasets will pinpoint the exact location where the affected cells reside. This information will enable formulation of strategies for future experiments designed to test their functions. To further her career development, she will take classes (e.g., MS, bioinformatics, statistics, grant writing, mentorship and career advancement) and seek additional training experiences (e.g., responsible conduct of research, diversity and outreach). To hone her communication skills, she will regularly give presentations at UCSF and national meetings. Her research and career development will be overseen by an outstanding team of senior faculty with the relevant expertise indicated: Dr. Linda Giudice (human uterine biology, endometriosis, infertility), Dr. Robert Blelloch (cancer biology and immunology, mouse placental biology) and Dr. Steven Hall (mass spectrometry, including instrumentation and data analysis). All have distinguished mentoring and training records; two are physician scientists (Drs. Giudice and Blelloch). Their commitment to the candidate and the enthusiastic support of her primary mentor, Dr. Fisher, ensure the success of the training plan and the eventual launch of the candidate’s independent career as a faculty member and principal investigator at a top-tier medical research institution.