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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应用总结

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

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

DOI：
10.1371/journal.pgen.1009412
发表时间：
2021-05
期刊：
PLoS genetics
影响因子：
4.5
作者：
Oura S;Koyano T;Kodera C;Horisawa-Takada Y;Matsuyama M;Ishiguro KI;Ikawa M
通讯作者：
Ikawa M

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

ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility.

DOI：
10.1073/pnas.2018355118
发表时间：
2021-02-09
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Shimada K;Park S;Miyata H;Yu Z;Morohoshi A;Oura S;Matzuk MM;Ikawa M
通讯作者：
Ikawa M

Proximity-dependent biotin labeling in testicular germ cells identified TESMIN-associated proteins.

睾丸生殖细胞中依赖性依赖性生物素标记鉴定出与TESMIN相关的蛋白。