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Current humanized mouse models for studying human immunology and HIV-1 immuno-pathogenesis

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Science China(Life Sciences) 2010年第2期53卷 195-203页

作者： MEISSNER Eric lineberger comprehensive cancer center Department of Microbiology and ImmunologySchool of MedicineUniversity of North Carolina at Chapel Hill

A robust animal model for "hypothesis-testing/mechanistic" research in human immunology and immuno-pathology should meet the following ***,it has well-studied hemato-lymphoid organs and target cells similar to those of ***,the human pathogens establish infection and lead to relevant ***,it is genetically inbred and can be manipulated via genetic,immunological and pharmacological *** human-tropic pathogens such as HIV-1 fail to infect murine cells due to the blocks at multiple steps of their life *** mouse with a reconstituted human immune system and other human target organs is a good candidate.A number of human-mouse chimeric models with human immune cells have been developed in the past 20 years,but most with only limited success due to the selective engraftment of xeno-reactive human T cells in hu-PBL-SCID mice or the lack of significant human immune responses in the SCID-hu Thy/Liv *** review summarizes the current understanding of HIV-1 immuno-pathogenesis in human patients and in SIV-infected primate *** also reviews the recent progress in the development of humanized mouse models with a functional human immune system,especially the recent progress in the immunodeficient mice that carry a defective gammaC ***/SCID/gammaC-/(NOG or NSG) or the Rag2-/-/gammaC-/double knockout (DKO) mice,which lack NK as well as T and B cells (NTB-null mice),have been used to reconstitute a functional human immune system in central and peripheral lymphoid organs with human CD34+ *** NTB-hu HSC humanized models have been used to investigate HIV-1 infection,immuno-pathogenesis and therapeutic *** models,with further improvements,will contribute to study human immunology,human-tropic pathogens as well as human stem cell biology in the tissue development and function in vivo.

关键词： Humanized mouse models HIV-1 NOD/SCID/gammaC-/- Rag2-/-/gammaC-/-

Regulatory T cells: immune suppression and beyond

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Cellular & Molecular Immunology 2010年第3期7卷 204-210页

作者： Yisong Y Wan lineberger comprehensive cancer center Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillSchool of MedicineNorth CarolinaNCUSA

Foxp3-expressing regulatory T cells(Tregs)were originally identified as critical in maintaining self-tolerance and immune *** immunosuppressive functions of Tregs are widely acknowledged and have been extensively *** studies have revealed many diverse roles of Tregs in shaping the immune system and the inflammatory *** review will discuss our efforts as well as the efforts of others towards understanding the multifaceted function of Tregs in immune regulation.

关键词： Foxp3 Treg immunosuppression and plasticity

An essential role for TAK1 in the contact hypersensitivity response

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Cellular & Molecular Immunology 2011年第4期8卷 315-324页

作者： Yan G Zhao Yunqi Wang Weidong Hao Yisong Y Wan department of Toxicology School of Public HealthPeking UniversityBeijingChina department of Microbiology and Immunology Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillNCUSA

Contact hypersensitivity(CHS)is a delayed-type hypersensitivity that can be induced by haptens,such as 2,4-dinitrofluorobenzene(DNFB).Innate and adaptive immunities are both important for the development of *** treat CHS-related diseases,such as allergic contact dermatitis,a disease prevalent in industrialized countries,ways of interfering with improper immune function during CHS responses need to be *** growth factor-b-activated kinase-1(TAK1),a member of mitogen-activated protein kinase kinase kinase family,is important for both innate and adaptive *** thus hypothesized that the CHS response could be inhibited by interfering with TAK1 *** a mouse model in which TAK1 deletion can be locally induced,we observed that TAK deficiency led to an impaired CHS response and was associated with defective T-cell expansion,activation and interferon(IFN)-c *** addition,we investigated the effect of deleting TAK1 specifically in dendritic cells(DC)on the CHS *** found that when TAK1 is deficient in DC,the CHS response was abolished and hapten-elicited T-cell responses were ***,this study demonstrates an essential role of TAK1 in the induction of CHS and suggests that targeting TAK1 could be a viable approach to treat CHS.

关键词： CHS DC 2,4-dinitrofluorobenzene(DNFB) TAK1

Phase‘separating'53BP1 from DSB repair

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Genes & Diseases 2023年第1期10卷 1-3页

作者： Youwei Zhang department of pharmacology Case Comprehensive Cancer CenterSchool of MedicineCase Western ReserveUniversityClevelandOH44106USA

Eukaryotic chromosomes occupy specific territories in the nucleus,which is key for genome stability and *** on the spatiotemporal organization and compaction pattern,eukaryotic chromatins can be recognized as transcriptionally active and loosely packed euchromatin in the nuclear interior and transcriptionally repressive and highly compacted heterochromatin at the nuclear periphery or around nucleoli(Fig.1).

关键词： function. separating interior

Cytosolic DNA sensing by cGAS:regulation,function,and human diseases

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1483-1497页

作者： Le Yu Pengda Liu lineberger comprehensive cancer center The University of North Carolina at Chapel HillChapel HillNCUSA department of Biochemistry and Biophysics The University of North Carolina at Chapel HillChapel HillNCUSA

Sensing invasive cytosolic DNA is an integral component of innate *** was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide,2/3/-cGAMP,as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory *** of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune *** the other hand,inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune ***,cGAS activation is tightly *** this review,we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation,including cGAS pre-and post-translational regulations,cGAS-binding proteins,and additional cGAS regulators such as ions and small *** will also reveal the pathophysiological function of cGAS and its product cGAMP in human *** hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.

关键词： diseases function cGAS

Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 methyltransferase activity

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Chinese Chemical Letters 2015年第4期26卷 455-458页

作者： Hacer Karatas Shirley Y.Lee Elizabeth C.Townsend Fang Cao Jing Xu Denzil Bernard Liu Liu Yali Dou Shaomeng Wang department of Medicinal Chemistry University of Michigan department of Internal Medicine University of Michigan department of Pathology University of Michigan comprehensive cancer center University of Michigan department of pharmacology University of Michigan

We described herein structure-based design, synthesis and evaluation of conformationally constrained, cyclic peptidomimetics to block the MLL1-WDR5 protein-protein interaction as inhibitors of the MLL1 histone methyltransferase activity. Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5 （Ki values 〈1 nmol/L） and function as antagonists of the MLL1 histone methyltransferase activity.

关键词： EpigeneticsMLL1 histone methyltransferaseWDRS-MLLI interactionSmall-molecule inhibitorsCyclic peptidomemtics

Immune plexins and semaphorins: old proteins, new immune functions

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Protein & Cell 2013年第1期4卷 17-26页

作者： Kelly Roney Eda Holl Jenny Ting University of Chapel Hill Department of Microbiology and Immunology22-004 Lineberger Comprehensive Cancer CenterCB7295Chapel HillNC 27599USA Duke University Department of SurgeryDurhamNC 27710USA

Plexins and semaphorins are a large family of proteins that are involved in cell movement and *** importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including the nervous(Nkyimbeng-Takwi and Chapoval,2011;McCormick and Leipzig,2012;Yaron and Sprinzak,2012),epithelial(Miao et al.,1999;Fujii et al.,2002),and immune systems(Takamatsu and Kumanogoh,2012)as well as diverse cell processes including angiogenesis(Serini et al.,2009;Sakurai et al.,2012),embryogenesis(Perala et al.,2012),and cancer(Potiron et al.,2009;Micucci et al.,2010).Plexins and semaphorins are transmembrane proteins that share a conserved extracellular semaphorin do-main(Hota and Buck,2012).The plexins and sema-phorins are divided into four and eight subfamilies respectively based on their structural *** are relatively small proteins containing the extracellular semaphorin domain and short intra-cellular *** contain the semaphorin domain and long intracellular tails(Hota and Buck,2012).The majority of plexin and semaphorin research has fo-cused on the nervous system,particularly the devel-oping nervous system,where these proteins are found to mediate many common neuronal cell processes including cell movement,cytoskeletal rearrangement,and signal transduction(Choi et al.,2008;Takamatsu et al.,2010).Their roles in the immune system are the focus of this review.

关键词： plexin semaphorin immune system den-dritic cell B cell T cell

A Combinative Assembly Strategy Inspired Reversibly Borate-Bridged Polymeric Micelles for Lesion-Specific Rapid Release of Anti-Coccidial Drugs

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Nano-Micro Letters 2020年第11期12卷 168-186页

作者： Hao Cheng Huaqing Zhang Gujun Xu Jin Peng Zhen Wang Bo Sun Djamila Aouameur Zhechen Fan Wenxin Jiang Jianping Zhou Yang Ding State Key Laboratory of Natural Medicines Department of PharmaceuticsChina Pharmaceutical University24 TongjiaxiangNanjing 210009People’s Republic of China department of Radiation Oncology Lineberger Comprehensive Cancer CenterCarolina Center for Cancer Nanotechnology ExcellenceCarolina Institute of NanomedicineUniversity of North Carolina at Chapel HillChapel HillNC 27599USA

Stimuli-triggered drug delivery systems hold vast promise in local infection treatment for the site-specific targeting and shuttling of ***,chitosan conjugates(SPCS)installed with sialic acid(SA)and phenylboronic acid(PBA)were synthesized,of which SA served as targeting ligand for coccidium and reversible-binding bridge for *** enhanced drug-loading capacity of SPCS micelles was attributed to a combination assembly from hydrophobicity-driving and reversible borate *** drug-loaded SPCS micelles shared superior biostability in upper gastrointestinal *** reaching the lesions,the borate bridges were snipped by carbohydrates under a higher pH followed by accelerated drug release,while SA exposure on micellar surface facilitated drug cellular internalization to eliminate parasites *** drugmicelles revealed an enhanced anti-coccidial capacity with a higher index of 185.72 compared with commercial *** dual-responsive combination of physicochemical assembly could provide an efficient strategy for the exploitation of stable,safe and flexible anti-infectious drug delivery systems.

关键词： Combinative assembly strategy Borate-bridged micelles Dual-stimuli-triggered release Lesion-specific location Coccidiosis control

Formal synthesis of(+)-tashiromine and study toward the total synthesis of(+)-stemoamide

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Chinese Chemical Letters 2013年第11期24卷 953-956页

作者： Yue-Jie Chen Rui-Yang Bao Xiao-Dong Zhang Ye-Feng Tang The comprehensive AIDS Research center Department of Pharmacology & Pharmaceutical Sciences School of Medicine Tsinghua University

An effcient formal synthesis of（＋）-tashiromine was achieved by employing an intermolecular asymmetric Mannich-type reaction as the key ***,a novel approach toward the total synthesis of（＋）-stemoamide through dyo... 详细信息

关键词： Stemoamide Tashiromine Dyotropic rearrangement b-Lactone Total synthesis