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Cellular and Molecular Basis of Human Primordial Germ Cell Specification

人类原始生殖细胞规格的细胞和分子基础

基本信息

批准号：
10396109
负责人：
Amander Clark
金额：
$ 32.87万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-20 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396109
关键词：
Address Animal Model Basic Science Binding CRISPR interference Cell Differentiation process Cell Line Cells ChIP-seq Child Chromatin DNA DNA Methylation Data Development Diagnosis Embryo Endoderm Enhancers Epigenetic Process Event Failure Fertility Fertilization Foundations Funding Future Gametogenesis Gene Expression Genome Germ Cells Goals Gonadal structure Grant Human Human Genome In Vitro Individual Infertility Knowledge Laboratories Life Life Cycle Stages Long Terminal Repeats Modeling Molecular Outcome Parents Process Publishing Reproduction Reproductive Health Research Research Proposals Retrotransposon Role SOX17 gene Scaffolding Protein Site Somatic Cell Specific qualifier value Stem Cell Research Structure of primordial sex cell TFAP2C gene Technology Time To specify Yolk Sac base blastocyst blastomere structure cell type demethylation design egg epigenome gastrulation human embryonic stem cell human pluripotent stem cell implantation induced pluripotent stem cell mutant natural Blastocyst Implantation prenatal reproductive self-renewal single-cell RNA sequencing sperm cell stem cell differentiation stem cells success unpublished works

项目摘要

Summary Human germline cells are essential for human reproduction as only these cells are capable of differentiating into gametes and transmitting DNA from parent to child. The pioneering cells of the human germline begin to form during prenatal life when a small number of embryonic cells are set aside around the time of embryo implantation and gastrulation in a process known as human primordial germ cell (hPGC) specification. This critical event in human germline cell development has a tremendous impact on an individual's future reproductive health as a failure in hPGC specification causes certain infertility. In this competitive renewal, the goal is to increase our fundamental knowledge on the cell and molecular basis of hPGC specification. Based on experimental results in the previous funding period, we aim to use human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) and the differentiation of hPGC-like cells (hPGCLCs) to achieve this goal. The overall hypothesis is that non-rodent and human-specific molecular events have evolved to regulate hPGC specification. Given that the focus of this grant is largely on regions of the genome that are uniquely human, this project is perfectly suited to the use of human cell-based models. In aim 1, the hypothesis to be addressed is that TFAP2C-bound human-specific retrotransposons regulate hPGC specification. In aim 2, the hypothesis to be addressed is that the expression of TFAP2C bound retrotransposons are regulated by targeted changes to the epigenome during hPGCLC differentiation. In the third aim, we will evaluate the relationship between TFAP2C and SOX17 in hPGC specification, with the hypothesis that TFAP2C functions upstream of SOX17 in a lineage primed hPGC progenitor to regulate specification of hPGCs. In summary, this competitive renewal builds upon success from the first funding period to contribute essential knowledge on the identification of new loci in the human genome that have evolved to regulate the specification and identity of hPGCs.

总结人类生殖细胞对人类生殖至关重要，因为只有这些细胞才能分化将DNA从父母传给孩子人类生殖细胞的先驱细胞开始胚胎干细胞是在出生前的生命中形成的，在胚胎发育的时候，着床和原肠胚形成的过程称为人类原始生殖细胞（hPGC）特化。这人类生殖细胞发育中的一个关键事件对个体的未来有着巨大的影响生殖健康作为hPGC特化的失败导致某些不孕症。在这次竞争性的更新中，目的是增加我们对hPGC特异性的细胞和分子基础的基础知识。基于根据上一个资助期的实验结果，我们的目标是利用人类胚胎干细胞（hESCs）和人诱导的多能干细胞（hiPSC）以及hPGC样细胞（hPGCLC）分化为实现这一目标。总的假设是，非啮齿动物和人类特异性分子事件进化来调节hPGC的特化。鉴于这项资助的重点主要是基因组的区域这个项目非常适合使用人类细胞模型。在目标1中，要解决假设是TFAP 2C结合的人特异性反转录转座子调节hPGC 规范.在目的2中，要解决的假设是TFAP 2C的表达结合了逆转录转座子在hPGCLC分化过程中受到表观基因组靶向变化的调节。在第三个目的，我们将评估TFAP 2C和SOX 17在hPGC规范中的关系，假设TFAP2C在谱系引发的hPGC祖细胞中的SOX 17上游起作用以调节 hPGC的规格。总之，这次竞争性续约是建立在第一次融资成功的基础上的。在这一时期，为确定人类基因组中新的基因座提供必要的知识，进化来调节hPGCs的特化和身份。