A5060873992- Sperm and Testicular Function
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Reproductive Biology and Fertility
- CRISPR and Genetic Engineering
- MicroRNA in disease regulation
- Circular RNAs in diseases
- Epigenetics and DNA Methylation
- Chemical Synthesis and Analysis
- Cancer-related molecular mechanisms research
- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- Crystallization and Solubility Studies
- RNA Research and Splicing
- X-ray Diffraction in Crystallography
- RNA Interference and Gene Delivery
- Multiple Myeloma Research and Treatments
- Renal and related cancers
- Advanced biosensing and bioanalysis techniques
- RNA modifications and cancer
- Catalytic Cross-Coupling Reactions
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Catalytic C–H Functionalization Methods
- Ovarian function and disorders
Baylor College of Medicine
2012-2024
Nanjing Agricultural University
2024
WuXi AppTec (United States)
2024
Shanghai Ninth People's Hospital
2024
Shanghai Jiao Tong University
2024
Nanjing Medical University
2017
University of Houston
2010
The University of Texas MD Anderson Cancer Center
2007-2008
Chinese University of Hong Kong
2004
MicroRNAs (miRNA) regulate complex patterns of gene expression, and the relevance altered miRNA expression to ovarian cancer remains be elucidated. By comprehensively profiling miRNAs mRNAs in serous tumors cell lines normal surface epithelium, we identified hundreds potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression miR-31, most underexpressed cancer, repressed predicted miR-31 targets including cycle regulator E2F2. MIR31 CDKN2A, which encode p14(ARF)...
MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes tumor suppressors in a variety human cancers, functional roles for individual not described clear cell ovarian carcinoma, an aggressive chemoresistant subtype cancer. We performed deep sequencing to comprehensively profile miRNA expression 10 cancer lines compared with normal surface epithelial...
Gene-expression analysis studies from Schultz et al. estimate that more than 2,300 genes in the mouse genome are expressed predominantly male germ line. As of their 2003 publication [Schultz N, Hamra FK, Garbers DL (2003) Proc Natl Acad Sci USA 100(21):12201-12206], functions majority these testis-enriched during spermatogenesis and fertilization were largely unknown. Since study by al., functional hundreds reproductive-tract-enriched have been performed, but there remain many for which...
Sperm-oocyte fusion is a critical event in mammalian fertilization, categorized by three indispensable proteins. Sperm membrane protein IZUMO1 and its counterpart oocyte JUNO make complex allowing sperm to interact with the oocyte, subsequent sperm-oocyte fusion. Oocyte tetraspanin CD9 also contributes However, process cannot be explained solely these essential factors. In this study, we focused on analyzing testis-specific gene 4930451I11Rik generated mutant mice using CRISPR/Cas9 system....
Significance Infertility is a global problem that afflicts 15% of couples, and in 50% cases, the attributing factor linked to men. Among these infertile men, 18% specifically exhibit decreased motility sperm (asthenozoospermia). Sperm dependent on formation functioning flagellum, modified cilium used for locomotion. Cilia are present almost every cell vertebrates essential proper organ functioning. Defects cilia lead severe syndromic diseases, termed ciliopathies, affecting numerous tissues...
Local control of sperm maturation Newly produced spermatozoa within the testis do not have fertilizing ability but become fully functional when they mature in epididymis. The development epididymis itself is dependent on testicular factors arriving via luminal flow. Improper signaling between and hypothesized to result male infertility. Kiyozumi et al. identified NELL2 as a protein that binds its receptor, ROS1, surface induces epididymal differentiation (see Perspective by Lord Oatley). In...
Significance Although formation of the mitochondrial sheath is a critical process in mature spermatozoa, molecular mechanisms involved genesis remain unclear. Using gene-manipulated mice, we discovered that ARMC12 regulates spatiotemporal “sperm dynamics” during through interactions with proteins MIC60, VDAC2, and VDAC3 as well testis-specific TBC1D21 GK2. In addition, demonstrated ARMC12-interacting GK2 are also essential for formation. Our paper sheds light on regulation sperm dynamics,...
DNA-encoded chemical libraries (DELs) provide a high-throughput and cost-effective route for screening billions of unique molecules binding affinity diverse protein targets. Identifying candidate compounds from these involves selection, DNA sequencing, measuring enrichment in sample pool barcodes. Successful detection potent binders is affected by many factors, including selection parameters, yields, library amplification, sequencing depth, errors, sizes, the chosen metric. To date, there...
A hypodiboric acid system for the reduction of nitro groups on DNA–chemical conjugates has been developed. This transformation provided good to excellent yields reduced amine product a variety functionalized aromatic, heterocyclic, and aliphatic compounds. DNA tolerance reaction conditions, extension decigram scale reductions, successful use in DNA-encoded chemical library synthesis, subsequent target selection are also described.
Significance While the emergence of gene modification technologies has produced major discoveries in biomedical sciences, recent development CRISPR/Cas9 system dramatically altered trajectory phenotypic analysis animal models. In this study, we identified male-specific clusters ( Cst and Pate ) family genes Gdpd Lypd found specific members to be required for male fertility, especially sperm fertilizing ability. Our findings support important roles these proteins function could used develop...
The development of a safe, effective, reversible, non-hormonal contraceptive method for men has been an ongoing effort the past few decades. However, despite significant progress on elucidating function key proteins involved in reproduction, understanding male reproductive physiology is limited by incomplete information genes expressed tissues, and no targets have so far reached clinical trials. To advance product development, further identification novel tract-specific leading to...
Significance To rapidly identify small-molecule lead compounds to target healthcare-associated proteases, we constructed a unique 9.8-million-membered protease-focused DNA-encoded chemical library. Affinity selection of this library with healthcare-relevant protease (i.e., thrombin, key protein necessary for blood coagulation) revealed potent inhibitors in the first screening attempt. Our results emphasize utility structurally focused approach uncover hits healthcare targets (e.g.,...
Significance There is no nonhormonal contraceptive pill for men, although hundreds of genes have been identified to play roles during spermatogenesis and fertilization in the male reproductive tract. To address absence drugs we established a DNA-encoded chemistry technology (DEC-Tec) platform. Our drug discovery campaign on BRDT, validated spermatogenic-specific target, yielded rapid potent specific inhibitors second bromodomain BRDT that unique binding characteristics BRDT-BD2 relative...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery poorly suited producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen billion DNA-encoded molecules en masse identify a potent class virus-specific inhibitors SARS-CoV-2...
Abstract Background Adenosine deaminase domain containing 2 (ADAD2) is a testis‐specific protein composed of double‐stranded RNA binding and non‐catalytic adenosine domain. A recent study showed that ADAD2 indispensable for the male reproduction in mice. However, detailed functions remain elusive. Objectives This aimed to investigate cause sterility Adad2 mutant mice understand molecular ADAD2. Materials methods homozygous mouse lines, –/– Δ/Δ , were generated by CRISPR/Cas9. Western...
DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify starting points for drug discovery. As robust transformation discovery, palladium-catalyzed C–N coupling is valuable synthetic method the construction of DECL matter; however, currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide bromide electrophiles. We developed conditions utilizing an N-heterocyclic carbene–palladium catalyst that extends this reaction...
Significance BET bromodomain inhibition is therapeutic in multiple diseases; however, pan-BET inhibitors have induced significant myelosuppression and gastrointestinal toxicity, perhaps due to of both tandem bromodomains (BD) all family members. However, selective just the first BD (BD1) phenocopies inhibitor activity preclinical models cancer, other diseases, and, for BRDT, testes a contraceptive effect. Here, we leveraged our multibillion-molecule collection DNA-encoded chemical libraries...
The bromodomain inhibitor (+)-JQ1 is a highly validated chemical probe; however, it exhibits poor in vivo pharmacokinetics. To guide efforts toward improving its pharmacological properties, we identified the primary metabolite using catalysis methods. Treatment of with tetrabutylammonium decatungstate under photochemical conditions resulted selective formation an aldehyde at 2-position thiophene ring [(+)-JQ1-CHO], which was further reduced to 2-hydroxymethyl analog [(+)-JQ1-OH]. Comparative...
Abstract High-throughput transcriptomics and proteomics approaches have recently identified a large number of germ cell–specific genes with many that remain to be studied through functional genetics approaches. Serine proteases (PRSS) constitute nearly one-third all proteases, and, in our bioinformatics screens, we are testis specific. In this study, chose focus on Prss44, Prss46, Prss54, which confirmed as specific mouse human. Based the analysis developmental expression mouse, four is...
Abstract Spermatozoa are produced in the testis but gain their fertilizing ability during epididymal migration. This necessary step sperm maturation includes posttranslational modification of membrane proteins that protein processing by proteases. However, molecular mechanism underpinning this remains unknown. In study, we focused on transmembrane serine protease 12 (Tmprss12). Based multi-tissue expression analysis PCR, Tmprss12 was specifically expressed testis, and its started day 10...
Abstract As the world population continues to increase unsustainable levels, importance of birth control and development new contraceptives are emerging. To date, male contraceptive options have been lagging behind those available women, few not satisfactory everyone. solve this problem, we searching for candidate target proteins non-hormonal contraceptives. Testis-specific appealing targets because they more likely be involved in reproduction their targeting by small molecules is predicted...
Abstract Background Ubiquitination is a post-translational modification required for number of physiological functions regulating protein homeostasis, such as degradation. The endoplasmic reticulum (ER) quality control system recognizes and degrades proteins no longer needed in the ER through ubiquitin–proteasome pathway. E2 E3 enzymes containing transmembrane domain have been shown to function control. UBE2J1 ubiquitin-conjugating enzyme reported be essential spermiogenesis at elongating...
A strategy for DNA-compatible, palladium-catalyzed hydroxycarbonylation of (hetero)aryl halides on DNA–chemical conjugates has been developed. This method generally provided the corresponding carboxylic acids in moderate to very good conversions iodides and bromides, poor chlorides. These conditions were further validated by application within a DNA-encoded chemical library synthesis subsequent discovery enriched features from selection experiments against two protein targets.
Abstract Mammalian spermatozoa are produced in the testis through spermatogenesis and matured epididymis to acquire fertilizing ability. Spermatozoa ejaculated migrate from uterus oviducts fuse with oocytes. Although over 2000 genes expressed abundantly mouse testes, responsible for male fertility not yet fully clarified. Here, we focused on two testis-enriched serine protease genes, Serine (Prss) 51 Prss55, which overlap their gene loci partially both mice humans. To characterize functions...
Infertility afflicts up to 15% of couples globally each year with men a contributing factor in 50% these cases. Globozoospermia is rare condition found infertile men, which characterized by defective acrosome biogenesis leading the production round-headed sperm. Here, we report that family sequence similarity 209 (Fam209) required for mouse FAM209 small transmembrane protein conserved among mammals. Loss Fam209 results fertility defects are secondary abnormalities during spermiogenesis,...