Transposons in Female Reproductive Health and Disease

女性生殖健康和疾病中的转座子

• 批准号: 8245711
• 负责人: Zev Williams
• 金额: $ 13.72万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245711
• 关键词: Address; Adult; Advisory Committees; Age; Area; Award; Biochemistry; Biological Assay; Biology; Clinical; Complex; Computational Biology; DNA Sequence; DNA Sequence Rearrangement; Development; Diagnosis; Diagnostics Research; Discipline of obstetrics; Disease; Doctor of Philosophy; Embryo; Ensure; Etiology; Failure; Feedback; Fellowship; Female; Fertility; Fetal Development; Funding; General Hospitals; Generations; Genetic; Genome; Genomic Instability; Genomics; Germ Cells; Goals; Gynecology; Hospitals; Human; Human Genome; Infertility; Instruction; Knock-out; Knockout Mice; Laboratories; Lead; Live Birth; Location; Mammals; Massachusetts; Measures; Medical center; Menopause; Mentors; Mobile Genetic Elements; Molecular Biology; Mus; Oocytes; Ovarian Tissue; Ovary; Phenotype; Physicians; Play; Positioning Attribute; Postdoctoral Fellow; Pregnancy; Principal Investigator; Proteins; RNA; Reproduction; Reproductive Biology; Reproductive Endocrinology; Reproductive Health; Reproductive Medicine; Research; Research Personnel; Residencies; Role; Scientist; Shapes; Small RNA; Spontaneous abortion; Testing; Therapeutic Human Experimentation; Time; Tissues; Training; Training Activity; Training Programs; United States National Institutes of Health; Universities; Wild Type Mouse; Woman; Women' s Health; Work; base; career; critical period; design; fetal; fly; genome-wide; innovation; interest; lectures; piRNA; premature; professor; public health relevance; reproductive development; skills

DESCRIPTION (provided by applicant): The proposal describes a five-year training program with the purpose of establishing a career as an NIH funded independent investigator in reproductive medicine and infertility. Dr. Williams has a longstanding interest in and commitment to reproductive biology and women's health and has a strong track record in molecular biology and reproductive medicine. He earned his PhD in Molecular Biology in the laboratory of Dr. Paul Wassarman, where he studied the mammalian oocyte. He completed residency training in obstetrics and gynecology at the Brigham and Women's Hospital/Massachusetts General Hospital and is in the last year of fellowship training in reproductive endocrinology and infertility at Weill-Cornell Medical Center. Over the course of this award period he will expand his proficiency in genomics, RNA biology, assay design and computational biology with the overarching goal of elucidating the effect of transposons on oocytes and fertility. The training program has been designed to ensure command of RNA and transposon biology as applied to female reproduction. Dr. Thomas Tuschl, a pioneer in the field of RNA biology, will mentor the principal investigator's scientific development. He is Professor of Biochemistry at The Rockefeller University and has trained and guided many postdoctoral fellows to independent research positions. Training activities will include instruction in assay design and lectures in RNA molecular biology and computational biology. A scientific advisory committee of exceptional basic and physician-scientists will provide ongoing feedback. Transposons are mobile genetic elements comprising nearly half of the human genome. Their replication can cause genetic damage and disease and must be suppressed in the oocyte. In flies and worms, a special class of small RNA molecules (piRNA) and proteins (PIWI) suppress transposons. The long-term goal of the study is to investigate the mechanism by which mammalian oocytes suppress transposons and the effect of transposons on female fertility. The central hypothesis is that replication of transposons in mammals can cause miscarriage and is normally suppressed by piRNA and PIWI proteins. The hypothesis will be tested by pursuing three specific aims, namely: (1) to determine whether human ovaries contains piRNA and PIWI proteins (2) to assess the phenotype of the PIWI knockout in the female mouse (3) to determine the rate of transposon replication in normal pregnancies and miscarriage. The approach is innovative because it proposes a new etiology of infertility and involves developing assay utilizing whole-genome analysis with second- generation DNA sequencing. The research is significant because it will explain how the oocyte protects its genome from transposons and provides a new avenue for fertility diagnosis and treatment. Dr. Tuschl's laboratory at Rockefeller University is an ideal setting for intensive training in a set of highly specialized scientific skills required to address this complex area of reproductive biology and prepare the principal investigator for an academic career in reproductive biology. PUBLIC HEALTH RELEVANCE: Nearly half of the human genome is composed of mobile genetic elements called transposons. The oocyte must suppress transposon replication because that causes damage to the genome that may result in miscarriage, infertility and premature. The purpose of this study is to determine how the oocyte suppresses transposons and the effect of transposons on female reproduction.

描述（由申请人提供）：该提案描述了一个为期五年的培训计划，其目的是作为 NIH 资助的生殖医学和不孕不育领域的独立研究者建立职业生涯。威廉姆斯博士对生殖生物学和妇女健康有着长期的兴趣和承诺，并在分子生物学和生殖医学方面拥有良好的记录。他在 Paul Wassarman 博士的实验室获得了分子生物学博士学位，在那里他研究了哺乳动物的卵母细胞。他在布莱根妇女医院/马萨诸塞州总医院完成了妇产科住院医师培训，并在威尔-康奈尔医学中心接受了生殖内分泌学和不孕不育方面的进修培训的最后一年。在此获奖期间，他将提高自己在基因组学、RNA 生物学、测定设计和计算生物学方面的熟练程度，总体目标是阐明转座子对卵母细胞和生育力的影响。 该培训计划旨在确保掌握应用于女性生殖的 RNA 和转座子生物学。 RNA 生物学领域的先驱 Thomas Tuschl 博士将指导首席研究员的科学发展。他是洛克菲勒大学生物化学教授，培训并指导了许多博士后研究员担任独立研究职位。培训活动将包括检测设计指导以及 RNA 分子生物学和计算生物学讲座。由杰出的基础科学家和医师科学家组成的科学咨询委员会将提供持续的反馈。 转座子是可移动的遗传元件，占人类基因组的近一半。它们的复制会导致遗传损伤和疾病，必须在卵母细胞中受到抑制。在果蝇和蠕虫中，一类特殊的小 RNA 分子 (piRNA) 和蛋白质 (PIWI) 会抑制转座子。该研究的长期目标是研究哺乳动物卵母细胞抑制转座子的机制以及转座子对女性生育力的影响。核心假设是，转座子在哺乳动物中的复制会导致流产，并且通常受到 piRNA 和 PIWI 蛋白的抑制。该假设将通过三个具体目标进行检验，即：(1) 确定人类卵巢是否含有 piRNA 和 PIWI 蛋白 (2) 评估雌性小鼠 PIWI 敲除的表型 (3) 确定正常妊娠和流产中转座子复制的速率。该方法具有创新性，因为它提出了不孕不育的新病因，并涉及利用全基因组分析和第二代 DNA 测序开发检测方法。这项研究意义重大，因为它将解释卵母细胞如何保护其基因组免受转座子的影响，并为生育诊断和治疗提供新途径。 Tuschl 博士位于洛克菲勒大学的实验室是对一系列高度专业化的科学技能进行强化培训的理想场所，这些技能需要解决生殖生物学这一复杂领域的问题，并为首席研究员在生殖生物学领域的学术生涯做好准备。 公共健康相关性：近一半的人类基因组由称为转座子的移动遗传元件组成。卵母细胞必须抑制转座子复制，因为这会对基因组造成损害，从而可能导致流产、不孕和早产。本研究的目的是确定卵母细胞如何抑制转座子以及转座子对女性生殖的影响。