Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.634
Filtrar
1.
Bioanalysis ; 14(5): 267-278, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35195037

RESUMO

Background: The degree of human hepatocyte replacement in chimeric mice with humanized liver has previously been shown to correlate with human plasma albumin measurements. However, there are no reports that directly compare the remaining endogenous mouse albumin with the newly expressed human albumin following engraftment. To better understand the disposition of serum albumin in PXB-mice, we developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to simultaneously quantitate both human and mouse albumin from plasma. Results: A robust correlation was observed between the serum human albumin levels measured by LC-MS/MS and the estimated replacement index of PXB-mice. Conclusion: All data were shown to be specific and suitable to accurately quantify both human and mouse albumin from plasma of chimeric mice with humanized livers.


Assuntos
Albumina Sérica Humana , Espectrometria de Massas em Tandem , Quimera , Cromatografia Líquida , Hepatócitos , Humanos , Fígado , Espectrometria de Massas em Tandem/métodos
2.
J Med Chem ; 65(15): 10217-10232, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35916496

RESUMO

Targeted protein degradation (TPD), represented by proteolysis-targeting chimera (PROTAC), has emerged as a novel therapeutic modality in drug discovery. However, the application of conventional PROTACs is limited to protein targets containing cytosolic domains with ligandable sites. Recently, nucleic-acid-based modalities, such as modified oligonucleotide mimics and aptamers, opened new avenues to degrade protein targets and greatly expanded the scope of TPD. Beyond constructing protein-degrading chimeras, nucleic acid motifs can also serve as substrates for targeted degradation. Particularly, the new type of chimeric RNA degrader termed ribonuclease-targeting chimera (RIBOTAC) has shown promising features in drug discovery. Here, we provide an overview of the newly emerging TPD strategies based on nucleic acids as well as new strategies for targeted degradation of nucleic acid (RNA) targets. The design strategies, case studies, potential applications, and challenges are focused on.


Assuntos
Ácidos Nucleicos , Quimera/metabolismo , Descoberta de Drogas , Proteínas/metabolismo , Proteólise , RNA/metabolismo
3.
BMC Infect Dis ; 22(1): 665, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915436

RESUMO

BACKGROUND: Patients with adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibodies (AIGAs) are susceptible to disseminated Mycobacterium avium complex (MAC) infections. M. chimaera, a newly identified MAC species, is distinguished from the others due to the reduced virulence. Previous cases of disseminated M. chimaera infection have been linked to cardiothoracic surgery. Reports of disseminated M. chimaera in patients without a history of cardiothoracic surgery are rare. CASE PRESENTATION: A 57-year-old Asian man, previously healthy, presented with fever, dry cough, exertional dyspnea, and decreased appetite. The delayed resolution of pneumonia despite antibiotic treatment prompted further imaging studies and biopsies from the lung and lymph node. The fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated intense uptake in lung consolidations and diffuse lymphadenopathy. Cultures of the specimens obtained from sputum, blood, stool, lung tissue, and lymph node grew M. chimaera. Further immunological evaluation disclosed the presence of neutralizing AIGAs, which possibly led to acquired immunodeficiency and disseminated M. chimaera infection. CONCLUSIONS: We herein present the first case of adult-onset immunodeficiency due to AIGAs complicated with disseminated M. chimaera infection. Further immunological evaluation, including AIGAs, may be warranted in otherwise healthy patients who present with disseminated mycobacterial infection.


Assuntos
Síndromes de Imunodeficiência , Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Adulto , Quimera , Humanos , Síndromes de Imunodeficiência/complicações , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/microbiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
4.
Pathol Oncol Res ; 28: 1610447, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832114

RESUMO

Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal. In this study, we first identified the correlation between high expression of BRD4 and overall survival of patients with AML. Targeted degradation of BRD2, BRD3, and BRD4 proteins by dBET1, a proteolysis-targeting chimera (PROTAC) against the bromodomain and extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), and MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes of AML. Furthermore, we determined that dBET1 treatment arrested cell cycling and enhanced apoptosis and c-MYC was identified as the downstream target. Collectively, our results indicated that dBET1 had broad anti-cancer effects on AML cell lines with different molecular lesions and provided more benefits to patients with AML.


Assuntos
Leucemia Mieloide Aguda , Proteínas Nucleares , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Quimera/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leucemia Mieloide Aguda/patologia , Proteínas Nucleares/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-myc , Fatores de Transcrição/metabolismo
5.
ACS Chem Biol ; 17(7): 1733-1744, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35793809

RESUMO

PROteolysis TArgeting Chimeras (PROTACs) use the ubiquitin-proteasome system to degrade a protein of interest for therapeutic benefit. Advances made in targeted protein degradation technology have been remarkable, with several molecules having moved into clinical studies. However, robust routes to assess and better understand the safety risks of PROTACs need to be identified, which is an essential step toward delivering efficacious and safe compounds to patients. In this work, we used Cell Painting, an unbiased high-content imaging method, to identify phenotypic signatures of PROTACs. Chemical clustering and model prediction allowed the identification of a mitotoxicity signature that could not be expected by screening the individual PROTAC components. The data highlighted the benefit of unbiased phenotypic methods for identifying toxic signatures and the potential to impact drug design.


Assuntos
Quimera , Ensaios de Triagem em Larga Escala , Quimera/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
6.
ChemistryOpen ; 11(7): e202200131, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35822913

RESUMO

Optimizing linker design is important for ensuring efficient degradation activity of proteolysis-targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein-of-interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid-phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates.


Assuntos
Quimera , Técnicas de Síntese em Fase Sólida , Peptídeos e Proteínas de Sinalização Intercelular , Ligantes , Proteólise
7.
Proc Natl Acad Sci U S A ; 119(31): e2120307119, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35858381

RESUMO

Bears are fascinating mammals because of their complex pattern of speciation and rapid evolution of distinct phenotypes. Interspecific hybridization has been common and has shaped the complex evolutionary history of bears. In this study, based on the largest population-level genomic dataset to date involving all Ursinae species and recently developed methods for detecting hybrid speciation, we provide explicit evidence for the hybrid origin of Asiatic black bears, which arose through historical hybridization between the ancestor of polar bear/brown bear/American black bears and the ancestor of sun bear/sloth bears. This was inferred to have occurred soon after the divergence of the two parental lineages in Eurasia due to climate-driven population expansion and dispersal. In addition, we found that the intermediate body size of this hybrid species arose from its combination of relevant genes derived from two parental lineages of contrasting sizes. This and alternate fixation of numerous other loci that had diverged between parental lineages may have initiated the reproductive isolation of the Asiatic black bear from its two parents. Our study sheds further light on the evolutionary history of bears and documents the importance of hybridization in new species formation and phenotypic evolution in mammals.


Assuntos
Quimera , Hibridização Genética , Ursidae , Animais , Quimera/genética , Genoma , Filogenia , Ursidae/genética
8.
J Med Chem ; 65(15): 10183-10194, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35881047

RESUMO

Dysregulation of transcription factors has been implicated in a variety of human diseases. However, these proteins have traditionally been regarded as undruggable and only a handful of them have been successfully targeted by conventional small molecules. Moreover, the development of intrinsic and acquired resistance has hampered the clinical use of these agents. Over the past years, proteolysis-targeting chimeras (PROTACs) have shown great promise because of their potential for overcoming drug resistance and their ability to target previously undruggable proteins. Indeed, several small molecule-based PROTACs have demonstrated superior efficacy in therapy-resistant metastatic cancers. Nevertheless, it remains challenging to identify ligands for the majority of transcription factors. Given that transcription factors recognize short DNA motifs in a sequence-specific manner, multiple novel approaches exploit DNA motifs as warheads in PROTAC design for the degradation of aberrant transcription factors. These PROTACs pave the way for targeting undruggable transcription factors with potential therapeutic benefits.


Assuntos
Quimera , Neoplasias , Quimera/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteólise , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
10.
BMC Biol ; 20(1): 167, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35879753

RESUMO

BACKGROUND: Chimeras are genetically mixed entities resulting from the fusion of two or more conspecifics. This phenomenon is widely distributed in nature and documented in a variety of animal and plant phyla. In corals, chimerism initiates at early ontogenic states (larvae to young spat) and results from the fusion between two or more closely settled conspecifics. When compared to genetically homogenous colonies (non-chimeras), the literature has listed ecological and evolutionary benefits for traits at the chimeric state, further positioning coral chimerism as an evolutionary rescue instrument. However, the molecular mechanisms underlying this suggestion remain unknown. RESULTS: To address this question, we developed field monitoring and multi-omics approaches to compare the responses of chimeric and non-chimeric colonies acclimated for 1 year at 10-m depth or exposed to a stressful environmental change (translocation from 10- to 2-m depth for 48h). We showed that chimerism in the stony coral Stylophora pistillata is associated with higher survival over a 1-year period. Transcriptomic analyses showed that chimeras lose transcriptomic plasticity and constitutively express at higher level (frontload) genes responsive to stress. This frontloading may prepare the colony to face at any time environmental stresses which explain its higher robustness. CONCLUSIONS: These results show that chimeras are environmentally robust entities with an enhanced ability to cope with environmental stress. Results further document the potential usefulness of chimeras as a novel reef restoration tool to enhance coral adaptability to environmental change, and confirm that coral chimerism can be an evolutionary rescue instrument.


Assuntos
Antozoários , Aclimatação , Animais , Antozoários/genética , Quimera , Larva/genética , Estresse Fisiológico/genética
11.
J Med Chem ; 65(14): 9507-9530, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35816671

RESUMO

Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To fully harness the potential of this technology, a growing paradigm toward enriching PROTACs with other therapeutic modalities has been proposed. Could researchers successfully combine two modalities to yield multifunctional PROTACs with an expanded profile? In this Perspective, we try to answer this question. We discuss how this possibility encompasses different approaches, leading to multitarget PROTACs, light-controllable PROTACs, PROTAC conjugates, and macrocycle- and oligonucleotide-based PROTACs. This possibility promises to further enhance PROTAC efficacy and selectivity, minimize side effects, and hit undruggable targets. While PROTACs have reached the clinical investigation stage, additional steps must be taken toward the translational development of multifunctional PROTACs. A deeper and detailed understanding of the most critical challenges is required to fully exploit these opportunities and decisively enrich the PROTAC toolbox.


Assuntos
Quimera , Ubiquitina-Proteína Ligases , Quimera/metabolismo , Descoberta de Drogas , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
12.
Int J Mol Sci ; 23(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35886887

RESUMO

In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in several studies, HDAC8 can be considered a potential target in the treatment of cancer forms such as childhood neuroblastoma. The present work describes the development of proteolysis targeting chimeras (PROTACs) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we investigated the HDAC8-degrading profiles of the synthesized PROTACs and their effect on the proliferation of neuroblastoma cells. The combination of in vitro screening and cellular testing demonstrated selective HDAC8 PROTACs that show anti-neuroblastoma activity in cells.


Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Neuroblastoma , Linhagem Celular Tumoral/metabolismo , Quimera/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Neuroblastoma/metabolismo , Proteólise , Proteínas Repressoras/metabolismo
13.
J Med Chem ; 65(12): 8091-8112, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35686733

RESUMO

In recent years, with the successful development of proteolysis-targeting chimeric molecules (PROTACs), the potential of heterobifunctional molecules to contribute to reenvisioning drug design, especially small-molecule drugs, has been increasingly recognized. Inspired by PROTACs, diverse heterobifunctional molecules have been reported to simultaneously bind two or more molecules and bring them into proximity to interaction, such as ribonuclease-recruiting, autophagy-recruiting, lysosome-recruiting, kinase-recruiting, phosphatase-recruiting, glycosyltransferase-recruiting, and acetyltransferase-recruiting chimeras. On the basis of the heterobifunctional principle, more opportunities for advancing drug design by linking potential effectors to a protein of interest (POI) have emerged. Herein, we introduce heterobifunctional molecules other than PROTACs, summarize the limitations of existing molecules, list the main challenges, and propose perspectives for future research directions, providing insight into alternative design strategies based on substrate-proximity-based targeting.


Assuntos
Quimera , Desenho de Fármacos , Quimera/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
14.
Eur J Med Chem ; 239: 114533, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-35728507

RESUMO

Epidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting Chimeras (PROTACs) and LYsosome Targeting Chimeras (LYTACs), take advantages of protein destruction mechanism in cells, which make up for shortcomings of traditional small molecular occupancy-driven inhibitors. PROTACs based heterobifunctional EGFR degraders were recently developed by making use of wild-type (WT) and mutated EGFR inhibitors. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the inhibitors that have been developed against WT/mutated EGFR, and then mainly focuses on the recent advances of EGFR-targeting degraders along with its limitations and unlimited prospects.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimera/metabolismo , Receptores ErbB , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Pulmonares/metabolismo , Lisossomos/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteólise
15.
J Med Chem ; 65(13): 8798-8827, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35763424

RESUMO

Proteolysis-targeting chimeras (PROTACs) is a fast-growing technology providing many strengths over inhibition of protein activity directly and is attracting increasing interest in new drug discovery and development. However, efficiently identifying potent and drug-like degraders is still challenging in the development of PROTACs. Complementary to traditional PROTACs, several emerging types of PROTACs, such as homobivalent PROTACs based on two E3 ligases (e.g., CRBN, VHL, MDM2, TRIM24), chemical- or biological-based trivalent/multitargeted PROTACs, and covalent PROTACs, are rising for targeted protein degradation. These new types of PROTACs have several advantages over the traditional PROTACs including high selectivity, low toxicity, better therapeutic effects, and so on. In this perspective, we will summarize the latest development of representative PROTACs focusing on research mainly in past 10 years and discuss their advantages and disadvantages. Moreover, the outlook and perspectives on the associated challenges and future directions will be provided.


Assuntos
Quimera , Ubiquitina-Proteína Ligases , Quimera/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
16.
Signal Transduct Target Ther ; 7(1): 181, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680848

RESUMO

PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin-proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article "PROTACs: great opportunities for academia and industry" in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020-2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.


Assuntos
Quimera , Ubiquitina-Proteína Ligases , Quimera/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
17.
J Vis Exp ; (184)2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35723473

RESUMO

As a classical model system of embryo biology, the chicken embryo has been used to investigate embryonic development and differentiation. Delivering exogenous materials into chicken embryos has a great advantage for studying gene function, transgenic breeding, and chimera preparation during embryonic development. Here we show the method of in ovo intravascular injection whereby exogenous materials such as plasmid vectors or modified primordial germ cells (PGCs) can be transferred into donor chicken embryos at early developmental stages. The results show that the intravascular injection through the dorsal aorta and head allows injected materials to diffuse into the whole embryo through the blood circulatory system. In the presented protocol, the efficacy of exogenous plasmid and lentiviral vector introduction, and the colonization of injected exogenous PGCs in the recipient gonad, were determined by observing fluorescence in the embryos. This article describes detailed procedures of this method, thereby providing an excellent approach to studying gene function, embryo and developmental biology, and gonad-chimeric chicken production. In conclusion, this article will allow researchers to perform in ovo intravascular injection of exogenous materials into chicken embryos with great success and reproducibility.


Assuntos
Galinhas , Células Germinativas , Animais , Animais Geneticamente Modificados , Embrião de Galinha , Galinhas/genética , Quimera , Reprodutibilidade dos Testes
18.
Bioorg Med Chem Lett ; 72: 128870, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35772635

RESUMO

Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen receptor is a key protein in the proliferation and survival of prostate cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology. PROTACs are hetero-bifunctional molecules where one end binds to a protein of interest and the other to an E3 ligase ligand, initiating the Ubiquitin-Proteasome Pathway for protein degradation. Two PROTACs with niclosamide as androgen receptor ligand and VHL-032 as the E3 ligase ligand have been designed and synthesized for suppressing proliferation of androgen receptor-positive prostate cancer cells via degrading androgen receptor. The in vitro antiproliferative assessment suggested that they can selectively suppress PC-3, LNCaP, and 22Rv1 prostate cancer cell proliferation, but cannot inhibit DU145 cell proliferation. However, the mechanism of both compounds in suppressing prostate cancer cell proliferation is not through the AR PROTAC mechanism because they did not degrade AR in our Western Blotting assay up to 1 µM.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Quimera/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Ligantes , Masculino , Niclosamida/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proteólise , Receptores Androgênicos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
19.
Cancer Lett ; 544: 215808, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-35764266

RESUMO

PROteolysis TArgeting Chimeras (PROTACs) degrade target proteins via the ubiquitin-proteasome system, providing novel insights into drug development for hematologic malignancies. PROTACs outperform conventional therapeutics and currently available small molecule inhibitors in terms of efficacy, tissue-and cell-selectivity, and side effect profile. Most importantly, PROTACs are a powerful tool for addressing "undruggable" oncogenic proteins. Despite their numerous benefits, PROTACs as therapeutics face many challenges not only in the design and synthesis but also in the evaluation of anticancer effects and clinical application. In this article, we focus on PROTACs that have demonstrated preclinical efficacy and clinical potential in the treatment of various hematologic malignancies in the last 5 years. We start with a brief overview of the functioning mechanism and major breakthroughs in this field. To provide a balanced perspective on PROTACs, we discuss the pros and cons of exploiting PROTACs for therapeutic purposes. Following that, we brainstorm ideas to optimize PROTACs for clinical application. More PROTACs will enter clinical trials soon, benefiting patients with hematologic malignancies.


Assuntos
Quimera , Neoplasias Hematológicas , Quimera/metabolismo , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
20.
Cell Rep ; 39(11): 110933, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35705028

RESUMO

Generation of new kidneys can be useful in various research fields, including organ transplantation. However, generating renal stroma, an important component tissue for structural support, endocrine function, and kidney development, remains difficult. Organ generation using an animal developmental niche can provide an appropriate in vivo environment for renal stroma differentiation. Here, we generate rat renal stroma with endocrine capacity by removing mouse stromal progenitor cells (SPCs) from the host developmental niche and transplanting rat SPCs. Furthermore, we develop a method to replace both nephron progenitor cells (NPCs) and SPCs, called the interspecies dual replacement of the progenitor (i-DROP) system, and successfully generate functional chimeric kidneys containing rat nephrons and stroma. This method can generate renal tissue from progenitors and reduce xenotransplant rejection. Moreover, it is a safe method, as donor cells do not stray into nontarget organs, thus accelerating research on stem cells, chimeras, and xenotransplantation.


Assuntos
Rim , Néfrons , Nicho de Células-Tronco , Células-Tronco , Animais , Diferenciação Celular , Quimera , Rim/citologia , Camundongos , Néfrons/citologia , Ratos , Células-Tronco/citologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...