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A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses. 含有检查点修饰剂的治疗性乙型肝炎病毒疫苗可增强 CD8+ T 细胞和抗病毒反应。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.181067
Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, ZhiQuan Xiang, Andrew D Luber, Sue L Currie, XiangYang Zhou, Hildegund Cj Ertl

In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8+ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8+ T cell frequencies in spleen and liver.

在从急性乙型肝炎病毒(HBV)感染发展为慢性 HBV(CHB)感染的患者中,CD8+ T 细胞无法清除病毒并受损。慢性乙型肝炎的功能性治愈可能需要与感染诱导的CD8+ T细胞反应不同的新的高功能CD8+ T细胞反应。在此,我们报告了一种 HBV 治疗性疫苗的临床前免疫原性和疗效,该疫苗包括单纯疱疹病毒 (HSV) 糖蛋白 D (gD),这是一种早期 T 细胞活化的检查点调节剂,可增强、扩大和延长 CD8+ T 细胞应答。我们开发了一种基于黑猩猩腺病毒血清型 6 (AdC6) 载体的治疗性 HBV 疫苗,称为 AdC6-gDHBV2,其靶标是病毒聚合酶 (pol) 的保守和高免疫原性区域以及融合到 HSV gD 中的核心抗原。该疫苗在小鼠体内进行了含 gD 和不含 gD 的免疫原性测试,并在腺相关病毒 (AAV)8-1.3HBV 载体模型中进行了抗病毒效力测试。在 gD 中编码 HBV 抗原的疫苗可激发强效、广泛的 CD8+ T 细胞反应。在代理 HBV 感染模型中,单次肌肉注射 AdC6-gDHBV2 可使循环 HBV DNA 拷贝(cps)和 HBV 表面抗原(HBsAg)显著持续下降;两者均与脾脏和肝脏中的 HBV 特异性 CD8+ T 细胞频率成反比。AdC6-gDHBV2 是首个单独使用就能显著降低 HBV 基因组拷贝和 HBsAg 水平的治疗性疫苗,即使在感染后数月才接种疫苗也是如此。
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引用次数: 0
Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders. 感染后遗症中的多巴胺受体自身抗体信号转导可区分运动障碍和神经精神障碍。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.164762
Chandra M Menendez, Jonathan Zuccolo, Susan E Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W Cunningham

Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea, and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine D2 receptor (D2R) signaling. However, AAb influence on dopamine D1 receptor (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia, a region of high dopamine receptor density. Here, we report a mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived monoclonal antibodies (mAbs), which induced both D1R G protein- and β-arrestin-transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders.

尽管越来越多的人认识到,与感染相关的神经精神疾病是全世界尚未解决的一个重大问题。A 组链球菌(GAS)感染可导致以运动障碍(如西登纳姆舞蹈症(SC))和神经精神障碍为特征的自身免疫后遗症。这些疾病的分子机制尚不完全清楚。我们之前的研究表明,自身抗体(AAbs)可以靶向多巴胺能神经元并增加多巴胺受体D2(D2R)信号传导。然而,AAb对多巴胺受体D1(D1R)活性的影响尚未得到充分探索。我们发现有证据表明,GAS 诱导的交叉反应性 AAb 会促进基底节(BGE)自身免疫性脑炎,而基底节是多巴胺受体密度较高的区域。在这里,我们报告了一种新的机制,即神经精神综合征可通过 D1R 和 D2R AAb 滴度、信号传导、接收者操作特征曲线(ROC)以及 D1R 和 D2R 自身反应表位的免疫反应的差异而与运动障碍区分开来。通过患者血清 AAb 和新型患者衍生 mAb 观察到了 D1R AAb 信号传导,它们可诱导 D1R G 蛋白和 -arrestin 转导信号。此外,患者AAb和mAb增强了由神经递质多巴胺介导的D1R信号转导机制。我们的研究结果表明,AAb介导的D1R信号转导可能有助于神经精神后遗症的发病机制,并为诊断和治疗GAS后遗症及相关疾病提供了新的选择。.
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引用次数: 0
BAFF promotes follicular helper T cell development and germinal center formation through BR3 signal. BAFF 通过 BR3 信号促进滤泡辅助性 T 细胞的发育和生殖中心的形成。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.183400
Ye Chen, Maogen Chen, Yu Liu, Qiang Li, Youqiu Xue, Liu Liu, Rongzhen Liang, Yiding Xiong, Jun Zhao, Jingrong Chen, Weidong Lin, Julie Wang, Yun Feng Pan, William Stohl, Song Guo Zheng

T follicular helper (Tfh) cells represent an important subset of CD4+ T cells that is crucial to the maturation and differentiation of B cells and the production of high-affinity antibodies. Because B cell activating-factor (BAFF), a vital B cell survival factor, is also crucial to B cell maturation and differentiation, we assessed the effects of BAFF on Tfh cell development and function. We demonstrated that deficiency of BAFF, but not of APRIL, markedly inhibited Tfh cell development, germinal center (GC) formation, and antigen-specific antibody production. The promoting effect of BAFF on Tfh cell development was dependent on expression of BR3 on T cells, and its promoting effect on GC formation was dependent on expression of BR3 on both T cells and B cells. BAFF directly promoted expression of the Tfh cell-characteristic genes via NF-κB signaling. This effect did need BR3 expression. Thus, BAFF not only has direct effects on B cells, but it also has direct effects on Tfh cell differentiation via engagement of BR3, which collectively promoted GC formation and production of high-affinity antibodies. This dual effect of BAFF on B cells and Tfh cells may help explain the clinical utility of BAFF antagonists in the management of certain autoimmune diseases.

T 滤泡辅助细胞(Tfh)是 CD4+ T 细胞的一个重要亚群,对 B 细胞的成熟和分化以及高亲和力抗体的产生至关重要。BAFF是一种重要的B细胞存活因子,对B细胞的成熟和分化也至关重要,因此我们评估了BAFF对Tfh细胞发育和功能的影响。我们证明,缺乏 BAFF(而非 APRIL)会明显抑制 Tfh 细胞的发育、生殖中心(GC)的形成和抗原特异性抗体的产生。BAFF对Tfh细胞发育的促进作用依赖于T细胞上BR3的表达,而其对GC形成的促进作用依赖于T细胞和B细胞上BR3的表达。BAFF 通过 NF-κB 信号直接促进 Tfh 细胞特征基因的表达。这种作用需要 BR3 的表达。因此,BAFF 不仅对 B 细胞有直接作用,而且还通过 BR3 的参与对 Tfh 细胞的分化有直接作用,从而共同促进 GC 的形成和高亲和性抗体的产生。BAFF 对 B 细胞和 Tfh 细胞的这种双重作用可能有助于解释 BAFF 拮抗剂在治疗某些自身免疫性疾病方面的临床用途。
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引用次数: 0
Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGF-β depletion. 通过消耗 TGFβ 靶向胰腺癌小鼠转移模型中的异质性肿瘤微环境
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.182766
Sophia Y Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Jianxin Wang, Haley Zlomke, Michael Loycano, Rulin Wang, Michael Pickup, William R Burns, Juan Fu, William L Hwang, Lei Zheng

The dual tumor-suppressive and -promoting functions of TGF-β signaling has made its targeting challenging. We examined the effects of TGF-β depletion by AVID200/BMS-986416 (TGF-β-TRAP), a TGF-β ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGF-β-TRAP potentiates the efficacy of anti-programmed cell death 1 (anti-PD-1) in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T cells to combination TGF-β-TRAP and anti-PD-1 treatment across several tumor models. Single-nuclear RNA sequencing suggested that TGF-β-TRAP modulates cancer-associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGF-β-TRAP may modulate the CCL5/CCR5 axis as well as costimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGF-β-TRAP and anti-PD-1 combination treatment. This study suggested that TGF-β depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into antitumor immune agonists in PDAC, supporting the validation of such effects in human specimens.

TGFβ 信号具有抑制肿瘤和促进肿瘤生长的双重功能,因此其靶向治疗具有挑战性。我们在此研究了通过TGFβ配体捕获剂AVID200/BMS-986416(TGFβ-TRAP)消耗TGFβ对不同器官特异性转移的胰腺导管腺癌(PDAC)鼠模型肿瘤微环境的影响。我们的研究表明,TGFβ-TRAP 在具有肝转移倾向的 PDAC 正位小鼠模型中增强了抗 PD-1 的疗效,显著减少了肝转移。我们进一步证明了细胞毒性效应 T 细胞在多个肿瘤模型中对 TGFβ-TRAP 和抗 PD-1 联合治疗的异质性反应。单核 RNA 序列分析表明,TGFβ-TRAP 可调节癌症相关成纤维细胞(CAF)的异质性,抑制中性粒细胞脱颗粒和 CD4+ T 细胞对中性粒细胞脱颗粒的反应。配体-受体分析表明,TGFβ-TRAP可调节CCL5-CCR5轴以及CAFs和髓系细胞的共刺激和检查点信号。值得注意的是,在TGFβ-TRAP和抗PD-1联合治疗后,CCR5的高表达配体从免疫抑制性的CCL5转变为CCL7和CCL8,这可能介导了CCR5的免疫激动活性。这项研究表明,TGFβ消耗可调节CAF的异质性,并有可能将PDAC中的CAFs和骨髓细胞重编程为抗肿瘤免疫激动剂,支持在人体标本中验证这种效应。
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引用次数: 0
S1P regulates intervertebral disc aging by mediating endoplasmic reticulum-mitochondrial calcium ion homeostasis. S1P 通过介导内质网-线粒体钙离子平衡调节椎间盘老化。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.177789
Bingjie Zheng, Xuyang Zhang, Xiangxi Kong, Jie Li, Bao Huang, Hui Li, Zhongyin Ji, Xiaoan Wei, Siyue Tao, Zhi Shan, Zemin Ling, Junhui Liu, Jian Chen, Fengdong Zhao

As the aging process progresses, age-related intervertebral disc degeneration (IVDD) is becoming an emerging public health issue. Site-1 protease (S1P) has recently been found to be associated with abnormal spinal development in patients with mutations and has multiple biological functions. Here, we discovered a reduction of S1P in degenerated and aging intervertebral discs, primarily regulated by DNA methylation. Furthermore, through drug treatment and siRNA-mediated S1P knockdown, nucleus pulposus cells were more prone to exhibit degenerative and aging phenotypes. Conditional KO of S1P in mice resulted in spinal developmental abnormalities and premature aging. Mechanistically, S1P deficiency impeded COP II-mediated transport vesicle formation, which leads to protein retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow and resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.

从机理上讲,S1P的缺乏阻碍了COP II介导的运输囊泡的形成,从而导致蛋白质滞留在内质网(ER)中,继而导致ER膨胀。ER膨胀增加了ER与线粒体之间的接触,破坏了ER到线粒体之间的钙流,导致线粒体功能障碍和能量代谢紊乱。最后,使用 2-APB 抑制钙离子通道,以及使用衰老药物达沙替尼和槲皮素(D + Q),可部分缓解 S1P 缺乏导致的衰老和退行性表型。总之,我们的研究结果表明,S1P是衰老过程中导致IVDD的一个关键因素,并强调了靶向S1P作为老年相关IVDD治疗方法的潜力。
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引用次数: 0
Analysis of CNS autoimmunity in genetically diverse mice reveals unique phenotypes and mechanisms. 对不同基因小鼠中枢神经系统自身免疫的分析揭示了独特的表型和机制。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.184138
Emily A Nelson, Anna L Tyler, Taylor Lakusta-Wong, Karolyn G Lahue, Katherine C Hankes, Cory Teuscher, Rachel M Lynch, Martin T Ferris, J Matthew Mahoney, Dimitry N Krementsov

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The 32 CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary-EAE (AR-EAE), accompanied by distinct immunopathology. Sex differences in EAE severity were observed in 6 strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity (Abcc4 and Gpc6) and AR-EAE (Yap1 and Dync2h1). This work expands the EAE phenotypic repertoire and identifies potentially novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.

多发性硬化症(MS)是一种复杂的疾病,其病程和进展具有显著的异质性。遗传学研究发现了许多与多发性硬化症风险相关的基因位点,但疾病进展的遗传学基础仍然难以捉摸。为了解决这个问题,我们利用了合作杂交(CC)这一基因多样化的小鼠品系面板和实验性自身免疫性脑脊髓炎(EAE)。所研究的 32 个 CC 株系涵盖了 EAE 严重程度、发展轨迹和表现形式的广泛范围,包括重度进展型、单相型、复发缓解型和轴旋转型 (AR)-EAE,并伴有不同的免疫病理。在六个品系中观察到了EAE严重程度的性别差异。定量性状位点分析揭示了不同EAE表型的不同遗传连锁模式,包括EAE严重程度和AR-EAE发病率。基于机器学习的方法优先选择了EAE严重程度(Abcc4和Gpc6)和AR-EAE(Yap1和Dync2h1)基因座的候选基因。这项工作扩大了 EAE 表型的范围,并确定了控制独特 EAE 表型的新基因座,支持了多发性硬化症病程的异质性由遗传变异驱动的假设。
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引用次数: 0
Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD. 可解释的机器学习揭示了上皮转录重新布线以及 Gelsolin 在慢性阻塞性肺病中的作用。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.180239
Justin Sui, Hanxi Xiao, Ugonna Mbaekwe, Nai-Chun Ting, Kaley Murday, Qianjiang Hu, Alyssa D Gregory, Theodore S Kapellos, Ali Öender Yildirim, Melanie Königshoff, Yingze Zhang, Frank Sciurba, Jishnu Das, Corrine R Kliment

Transcriptomic analyses have advanced the understanding of complex disease pathophysiology including chronic obstructive pulmonary disease (COPD). However, identifying relevant biologic causative factors has been limited by the integration of high dimensionality data. COPD is characterized by lung destruction and inflammation, with smoke exposure being a major risk factor. To define previously unknown biological mechanisms in COPD, we utilized unsupervised and supervised interpretable machine learning analyses of single-cell RNA-Seq data from the mouse smoke-exposure model to identify significant latent factors (context-specific coexpression modules) impacting pathophysiology. The machine learning transcriptomic signatures coupled to protein networks uncovered a reduction in network complexity and new biological alterations in actin-associated gelsolin (GSN), which was transcriptionally linked to disease state. GSN was altered in airway epithelial cells in the mouse model and in human COPD. GSN was increased in plasma from patients with COPD, and smoke exposure resulted in enhanced GSN release from airway cells from patients with COPD. This method provides insights into rewiring of transcriptional networks that are associated with COPD pathogenesis and provides a translational analytical platform for other diseases.

转录组分析促进了对包括慢性阻塞性肺病(COPD)在内的复杂疾病病理生理学的了解。然而,由于需要整合高维数据,识别相关的生物致病因素受到了限制。慢性阻塞性肺病以肺部破坏和炎症为特征,烟雾暴露是其主要风险因素。为了确定慢性阻塞性肺病的新型生物学机制,我们利用无监督和有监督的可解释机器学习分析方法,对来自黄金标准小鼠烟雾暴露模型的单细胞-RNA 测序数据进行分析,以确定影响病理生理学的重要潜在因素(特定上下文共表达模块)。机器学习转录组特征与蛋白质网络相结合,发现了网络复杂性的降低和肌动蛋白相关凝胶酶原(GSN)的新型生物学改变,而凝胶酶原与疾病状态存在转录关联。在小鼠模型和人类慢性阻塞性肺病患者的气道上皮细胞中,GSN发生了改变。慢性阻塞性肺病患者血浆中的 GSN 增加,烟雾暴露导致慢性阻塞性肺病患者气道细胞中 GSN 释放增加。这种方法有助于深入了解与慢性阻塞性肺病发病机制相关的转录网络的重新布线,并为其他疾病提供了一个新的分析平台。
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引用次数: 0
Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice. 普肯耶细胞特异性 SEL1L-HRD1 内质网相关降解缺陷会导致小鼠进行性小脑共济失调。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.174725
Mauricio Torres, Brent Pederson, Hui Wang, Liangguang Leo Lin, Huilun Helen Wang, Amara Bugarin-Lapuz, Zhen Zhao, Ling Qi

Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell-specific deletion of SEL1L (Sel1LPcp2Cre) exhibited motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy analysis revealed dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Finally, loss of Purkinje cells was associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellums of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.

最近的研究发现,SEL1L-HRD1 ER相关降解(ERAD)的多种遗传变异存在于神经发育障碍和运动功能障碍(包括共济失调)患者中。然而,SEL1L-HRD1 ERAD在共济失调发病机制中的相关性和重要性仍有待探索。在这里,我们发现普金叶细胞中 SEL1L 的缺乏会导致早发的进行性小脑共济失调,并且随着年龄的增长,普金叶细胞会逐渐丧失。Purkinje细胞特异性缺失SEL1L(Sel1LPcp2Cre)的小鼠在9周龄左右开始出现运动功能障碍。透射电子显微镜(TEM)分析显示,成年 Sel1LPcp2Cre 小鼠的浦肯野细胞内存在扩张的 ER 和破碎的细胞核,这表明 ER 平衡发生了改变并导致细胞死亡。最后,在Sel1LPcp2Cre小鼠的小脑中,Purkinje细胞的丧失与颗粒细胞的继发性神经变性以及星形胶质细胞的强力激活和小胶质细胞的增殖有关。这些数据证明了浦肯野细胞中的SEL1L-HRD1 ERAD在小脑共济失调发病机制中的重要病理生理作用。
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引用次数: 0
All-in-one AAV-mediated Nrl gene inactivation rescues retinal degeneration in Pde6a mice. 一体化 AAV 介导的 Nrl 基因失活可挽救 Pde6a 小鼠的视网膜变性。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-05 DOI: 10.1172/jci.insight.178159
Zhiquan Liu, Siyu Chen, Chien-Hui Lo, Qing Wang, Yang Sun

Retinitis pigmentosa (RP) is a complex group of inherited retinal diseases characterized by progressive death of photoreceptor cells and eventual blindness. Pde6a, which encodes a cGMP-specific phosphodiesterase, is a crucial pathogenic gene for autosomal recessive RP (RP43); there is no effective therapy for this form of RP. The compact CRISPR/SaCas9 system, which can be packaged into a single adeno-associated virus, holds promise for simplifying effective gene therapy. Here, we demonstrated that all-in-one AAV-SaCas9-mediated Nrl gene inactivation can efficiently prevent retinal degeneration in a RP mouse model with Pde6anmf363/nmf363 mutation. We screened single guide RNAs (sgRNAs) capable of efficiently editing mouse Nrl gene in N2a cells and then achieved effective gene editing by using a single AAV to co-deliver SaCas9 and an optimal Nrl-sg2 into the mouse retina. Excitingly, in vivo inactivation of Nrl improved photoreceptor cell survival and rescued retinal function in treated Pde6a deficient mice. Thus, we showed that a practical, gene-independent method, AAV-SaCas9-mediated Nrl inactivation, holds promise for future therapeutic applications in patients with RP.

视网膜色素变性(RP)是一组复杂的遗传性视网膜疾病,其特点是感光细胞进行性死亡并最终失明。Pde6a编码一种cGMP特异性磷酸二酯酶,是常染色体隐性视网膜色素变性(RP43)的重要致病基因;目前还没有治疗这种视网膜色素变性的有效方法。CRISPR/SaCas9系统体积小巧,可封装在单个腺相关病毒中,有望简化有效的基因治疗。在这里,我们证明了一体化 AAV-SaCas9 介导的 Nrl 基因失活可以有效预防 Pde6anmf363/nmf363 突变的 RP 小鼠模型的视网膜变性。我们筛选出了能在 N2a 细胞中有效编辑小鼠 Nrl 基因的单导 RNA(sgRNA),然后使用单一 AAV 将 SaCas9 和最佳 Nrl-sg2 共同送入小鼠视网膜,实现了有效的基因编辑。令人兴奋的是,体内Nrl失活改善了光感受器细胞的存活率,并挽救了Pde6a缺陷小鼠的视网膜功能。因此,我们发现,AAV-SaCas9 介导的 Nrl 失活是一种不依赖基因的实用方法,未来有望应用于 RP 患者的治疗。
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引用次数: 0
BPDCN MYB fusions regulate cell cycle genes, impair differentiation and induce myeloid-dendritic cell leukemia. BPDCN MYB融合调节细胞周期基因,损害分化并诱发髓系树突状细胞白血病。
IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-05 DOI: 10.1172/jci.insight.183889
Christopher Ag Booth, Juliette M Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A DeCaprio, Andrew A Lane

MYB fusions are recurrently found in select cancers, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared to other blood cancers, and in some patients are the only obvious somatic mutation detected. This suggests they may alone be sufficient to drive dendritic cell transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but mechanistically how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that in BPDCN leukemogenesis, MYB switches from being a regulator of dendritic cell lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in BPDCN patients increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired dendritic cell differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.

MYB 融合经常出现在某些癌症中,包括预后不良的急性白血病--浆细胞性树突状细胞肿瘤(BPDCN)。与其他血癌相比,它们在 BPDCN 中明显富集,而且在某些患者中是唯一检测到的明显体细胞突变。这表明它们本身就足以驱动树突状细胞的转化。据推测,MYB融合会改变MYB的正常转录因子活性,但人们对它们如何促进白血病发生的机理却知之甚少。利用 CUT&RUN 染色质分析,我们发现在 BPDCN 白血病发生过程中,MYB 从树突状细胞系基因的调控因子转变为异常调控 G2/M 细胞周期控制基因。在 BPDCN 患者中发现的 MYB 融合体增加了这些位置 DNA 结合的幅度,这与 BPDCN 相关基因表达的变化有关。此外,MYB融合体在体内的表达会损害树突状细胞的分化并诱导转化,从而产生髓系-树突状急性白血病小鼠模型。在治疗方面,我们提出的证据表明,全反式维甲酸(ATRA)可导致MYB蛋白缺失和BPDCN细胞死亡。
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