Functional genomics and DEC-Tec to identify germ cell-specific contraceptives

功能基因组学和 DEC-Tec 鉴定生殖细胞特异性避孕药

基本信息

批准号：
10164823
负责人：
MARTIN M. MATZUK
金额：
$ 121万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164823
关键词：
Acrosome Advisory Committees Affinity Applications Grants Area Binding Bioavailable Biochemistry CRISPR/Cas technology Chemistry Clinical Trials Contraceptive Agents Contraceptive methods Country DNA Data Development Diagnosis Engineering Enzymes Epididymis Evaluation Female Fertility Fertilization Future Genomic DNA Genomic approach Germ Cells Goals Grant Health Health Care Costs Healthcare In Vitro Infertility Integral Membrane Protein International Lead Libraries Ligands Medicine Meiosis Mission Molecular Mus National Institute of Child Health and Human Development Oocytes Oral Contraceptives Organic Chemistry PPP3CC gene PPP3R2 gene Pathway interactions Pharmaceutical Preparations Pharmacology Planets Population Population Growth Pregnancy Process Program Development Program Research Project Grants Proteins Public Health Reproductive Biology Research Research Personnel Role Scientist Series Serine Protease Signaling Protein Sperm Maturation Sperm Motility Spermatogenesis Strategic Planning Technology Testing Testis Translating United States Universities Vision Woman Zona Pellucida abortion base cell motility college contraceptive target drug discovery druggable target egg follow-up functional genomics in vivo inhibitor/antagonist innovation male male fertility member men mouse genome multidisciplinary novel novel therapeutics pill pre-clinical programs prototype reproductive reproductive tract reversible contraceptive side effect small molecule sperm cell sperm function unintended pregnancy

项目摘要

SUMMARY OF P01 APPLICATION The Strategic Plan 2000 of NICHD states that uncontrolled fertility “is one of the most pressing public health challenges facing the world today,” and in 2014, NICHD identified contraception as one of the three priority areas in implementing its scientific vision. Unintended pregnancies are a major health problem worldwide, and in our country, 45% of pregnancies are unintended, 42% of these end in abortion, and the annual healthcare costs are more than $7 billion. However, there is no oral contraceptive pill for men. Our multidisciplinary groups at Baylor College of Medicine and Osaka University have joined forces for the intellectual, technical, and pharmacologic challenge of defining germ cell-specific pathways essential for fertility and developing high- quality preclinical compounds to target spermatogenesis, sperm maturation, motility, and/or fertilization as effective non-hormonal contraceptives for men and women. Our Program Project Grant application describes a new P01 program based on decades of scientific interactions and discoveries of our investigators. The proposed male fertility-directed and contraceptive-directed studies will use state-of-the-art functional genomics and drug discovery approaches to reach our goals. We propose three projects that focus on testis-specific, epididymis-specific, and/or fertilization-specific targets for which optimal small-molecule ligands have yet to be identified and for which mechanistic data are lacking. The proposal includes an Administrative Core that will oversee the finances and stimulate scientific and translational advances of our team. Central to the projects and our team goals of developing novel contraceptives is our DNA-Encoded Chemistry Technology (DEC-Tec) Core that will 1) screen our candidate contraceptive targets against unique billion-compound libraries, 2) produce lead compounds and probes for in vitro mechanistic studies and in vivo contraceptive testing in mice, and 3) identify preclinical candidates for evaluation in clinical trials in men or women. The major innovative aspects of this P01 proposal are 1) our collective application of CRISPR/Cas9 to expeditiously engineer the mouse genome to interrogate male fertility pathways, and 2) our application of DEC-Tec to economically and rapidly identify high-affinity probes and lead compounds to target our reproductive tract-required proteins for evaluation of function and proof-of-concept contraceptive analysis in vivo. The primary objective of our P01 studies is to have multiple bioavailable, effective, and reversible contraceptives directed at novel reproductive targets for testing in men or women within five years. This novel research program will support an internationally-recognized team of scientists with complementary expertise in organic chemistry, biochemistry, functional genomics, and reproductive biology, and has the potential of a huge healthcare payoff by identifying key male fertility pathways and creating unique contraceptives for reversible disruption of essential spermatogenetic, sperm maturation, and fertilization pathways.

P01 申请摘要 NICHD 2000 年战略计划指出，不受控制的生育“是最紧迫的公共卫生问题之一” 当今世界面临的挑战”，2014 年，NICHD 将避孕确定为三个优先事项之一意外怀孕是世界范围内的一个主要健康问题。在我国，45% 的怀孕是意外怀孕，其中 42% 以堕胎告终，每年的医疗保健成本超过 70 亿美元，但我们的多学科小组还没有针对男性的口服避孕药。贝勒医学院和大阪大学联手开发智力、技术和定义生育力和发育高水平所必需的生殖细胞特异性途径的药理学挑战以精子发生、精子成熟、活力和/或受精为目标的优质临床前化合物我们的计划项目拨款申请描述了针对男性和女性的有效非激素避孕药。新的 P01 计划基于数十年的科学互动和我们研究人员的发现。拟议的男性生育导向和避孕导向研究将使用最先进的功能基因组学我们提出了三个专注于睾丸特异性的项目。附睾特异性和/或受精特异性靶点尚未找到最佳小分子配体该提案包括一个管理核心，该核心将被识别并缺乏机械数据。监督财务并促进我们团队的科学和转化进步是项目的核心。我们团队开发新型避孕药的目标是我们的 DNA 编码化学技术 (DEC-Tec) 核心将 1) 根据独特的十亿化合物库筛选我们的候选避孕靶标，2) 生产用于体外机制研究和小鼠体内避孕测试的先导化合物和探针， 3）确定临床前候选者，以在男性或女性的临床试验中进行评估。该 P01 提案的各个方面是 1) 我们集体应用 CRISPR/Cas9 来快速设计小鼠基因组来询问雄性生育途径，以及 2) 我们将 DEC-Tec 应用于经济和快速识别高亲和力探针和先导化合物来靶向我们的生殖道所需的蛋白质体内功能评估和概念验证避孕分析我们 P01 的主要目标。研究的目的是找到多种生物可利用的、有效的、可逆的避孕药具，针对新型生殖这项新颖的研究计划将支持五年内对男性或女性进行测试的目标。国际公认的科学家团队，在有机化学方面具有互补的专业知识，生物化学、功能基因组学和生殖生物学，具有巨大的潜力通过确定关键的男性生育途径并为女性创造独特的避孕方法来获得医疗保健回报重要的精子发生、精子成熟和受精途径的可逆性破坏。

项目成果

期刊论文数量（80）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyp1a2-knockout increases the systemic exposure of a serotonin and norepinephrine reuptake inhibitor duloxetine in mice.

Cyp1a2 敲除增加了小鼠体内血清素和去甲肾上腺素再摄取抑制剂度洛西汀的全身暴露。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Qin,Xuan;Xie,Cen;Hakenjos,JohnM;Mackenzie,KevinM;Barzi,Mercedes;Nyshadham,Pranavanand;Khalil,SalehM;Bissig,Karl-Dimiter;Gonzalez,FrankJ;Matzuk,MartinM;Li,Feng
通讯作者：
Li,Feng

Engineered CRISPR-Cas9 nuclease with expanded targeting space.

DOI：
10.1126/science.aas9129
发表时间：
2018-09-21
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Nishimasu H;Shi X;Ishiguro S;Gao L;Hirano S;Okazaki S;Noda T;Abudayyeh OO;Gootenberg JS;Mori H;Oura S;Holmes B;Tanaka M;Seki M;Hirano H;Aburatani H;Ishitani R;Ikawa M;Yachie N;Zhang F;Nureki O
通讯作者：
Nureki O

KCTD19 and its associated protein ZFP541 are independently essential for meiosis in male mice.