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申请的摘要 NICHD 2000年战略计划指出，不受控制的生育能力“是公共卫生最紧迫的一种 “当今世界面临的挑战”，“ 2014年，NICHD将避孕措施确定为三个优先事项之一实施其科学愿景的领域。意外怀孕是全球主要的健康问题，在我国，有45％的怀孕是意想不到的，其中42％的堕胎结束了，年度医疗保健成本超过70亿美元。但是，男性没有口服避孕药。我们的多学科群体在贝勒医学院和大阪大学，已经为知识，技术和定义生殖细胞特异性途径的药理学挑战，对生育至关重要质量临床前化合物靶向精子发生，精子成熟，运动性和/或受精为男女有效的非荷尔蒙避孕药。我们的计划项目授予申请说明新的P01计划基于数十年的科学互动和研究人员的发现。拟议的男性生育能力和避孕导向的研究将使用最先进的功能基因组学和药物发现的方法以实现我们的目标。我们提出了三个专注于特定于睾丸的项目，附睾特异性和/或受精的特异性靶标，最佳的小分子配体尚未为确定并缺乏机械数据。该提案包括一个行政核心监督财务状况并刺激我们团队的科学和翻译进步。项目的中心我们开发新型避孕药的团队目标是我们的DNA编码化学技术（DEC-TEC）核心将1）筛选我们的候选避孕目标针对独特的十亿个混合图书馆，2）在小鼠的体外机械研究和体内避孕试验中产生铅化合物和问题， 3）确定男性或女性临床试验中评估的临床前候选者。主要的创新该P01提案的各个方面是1）我们集体应用CRISPR/CAS9来迅速设计小鼠基因组询问男性生育途径，2）我们将DEC-TEC应用于经济和迅速识别高亲和力问题并导致化合物，以靶向我们的生殖道蛋白在体内评估功能和概念概念避孕分析。我们P01的主要目标研究应具有多种生物利用，有效和可逆的避孕药，该避孕药针对新型生殖五年内男性或女性测试的目标。这个新颖的研究计划将支持国际认可的科学家团队具有有机化学专业知识，生物化学，功能基因组学和生殖生物学，并具有巨大的潜力通过确定关键的男性生育道路并为必需的精子发生，精子成熟和受精途径的可逆破坏。

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.