NYAP1

更新于：2025-05-07

基本信息

别名

C7orf51、FLJ37538、KIAA1486L

+ [3]

简介

Activates PI3K and concomitantly recruits the WAVE1 complex to the close vicinity of PI3K and regulates neuronal morphogenesis.

关联

100 项与 NYAP1 相关的临床结果

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100 项与 NYAP1 相关的转化医学

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0 项与 NYAP1 相关的专利（医药）

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项与 NYAP1 相关的文献（医药）

2024-12-01·Alzheimer's & Dementia

Sex‐stratified GWAS for Alzheimer’s Disease Reveals African Ancestry Risk variants in Men

Article

作者: Guen, Yann Le ; Greicius, Michael D ; Napolioni, Valerio ; Belloy, Michael E. ; Reid, Danielle M.

AbstractBackgroundSeveral studies have indicated sex‐specific genetic risk for Alzheimer’s disease (AD), but these were centered on non‐Hispanic White individuals of European ancestry. We sought to identify sex‐specific genetic variants for AD in non‐Hispanic and Hispanic subjects of admixed African ancestry.MethodParticipants were ages 60+, of African ancestry (≥25%), and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed or whole genome sequencing (WGS). Genome‐wide association studies (GWAS) were performed per data type, sex, and Hispanic/non‐Hispanic status (Table‐1), requiring genotyping rate ≥80% and minor allele frequency ≥1%, followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). A sex‐by‐SNP interaction model was also evaluated. GWAS performed multiple linear regression on an AD‐age score (Le Guen & Belloy et al. 2021; Figure‐1), adjusting for APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Variants were filtered to be covered on at least half of the individuals per stratum.ResultWe found 3 genome‐wide significant loci in men (Figure‐2) with lead variants 1) rs74853649 ∼85kb downstream of FHIT, 2) rs73411425 in the PILRA/ZCWPW1/NYAP1 AD risk locus, and 3) rs3736450 intronic on WWOX. Despite that rs73411425 is within a known locus, the variant is novel. Notably, all three variants showed significant sex‐by‐SNP interactions and were specific to African rather than European ancestry (Table‐2). Further, in men, we also observed a suggestive association intronic on RBFOX1, which was previously implicated as a risk gene harboring variants associated with higher amyloid burden in brain (Raghavan et al. 2020), with strongest effect sizes in African‐American individuals (those samples were independent of the current data).ConclusionThe study is an initial exploration of sex‐specific genetic effects in African ancestry individuals and warrants replication in larger data. Importantly, we show the relevance of expanding beyond non‐Hispanic white samples for sex dimorphism research, identifying male‐specific risk variants that have elevated frequencies in African ancestry, while being rare in other ancestries. In ongoing work, we are performing cross‐ancestry meta‐analyses of sex‐stratified GWAS followed by sex‐stratified omics integration to increase power to uncover sex‐specific genes relevant to AD.

2023-10-01·Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Top Alzheimer's disease risk allele frequencies differ in HABS‐HD Mexican‐ versus Non‐Hispanic White Americans

Article

作者: Rao, Sumedha ; O'Bryant, Sid ; Barber, Robert Clinton ; Phillips, Nicole ; Reid, Danielle Marie ; Subasinghe, Kumudu ; Gutierrez, John ; Zhou, Zhengyang ; Silzer, Talisa ; Jomaa, Rodwan ; Housini, Mohammad

AbstractINTRODUCTION: Here we evaluate frequencies of the top 10 Alzheimer's disease (AD) risk alleles for late‐onset AD in Mexican American (MA) and non‐Hispanic White (NHW) American participants enrolled in the Health and Aging Brain Study–Health Disparities Study cohort.METHODS: Using DNA extracted from this community‐based diverse population, we calculated the genotype frequencies in each population to determine whether a significant difference is detected between the different ethnicities. DNA genotyping was performed per manufacturers’ protocols.RESULTS: Allele and genotype frequencies for 9 of the 11 single nucleotide polymorphisms (two apolipoprotein E variants, CR1, BIN1, DRB1, NYAP1, PTK2B, FERMT2, and ABCA7) differed significantly between MAs and NHWs.DISCUSSION: The significant differences in frequencies of top AD risk alleles observed here across MAs and NHWs suggest that ethnicity‐specific genetic risks for AD exist. Given our results, we are advancing additional projects to further elucidate ethnicity‐specific differences in AD.

2021-12-01·Alzheimer's & dementia : the journal of the Alzheimer's Association

Functional exploration of AGFG2, a novel player in the pathology of Alzheimer disease.

Article

作者: McDade, Eric ; Cruchaga, Carlos ; Perrin, Richard J ; Benitez, Bruno A ; Wang, Fengxian ; Eteleeb, Abdallah ; Bateman, Randall J ; Karch, Celeste M ; Fernandez, Maria Victoria ; Gentsch, Jen ; Harari, Oscar ; Morris, John C ; Martinez, Rita ; Norton, Joanne ; Budde, John P

BACKGROUNDThere are three main clinical presentations in Alzheimer disease (AD) with diversity in phenotype, onset and progression of clinical symptoms: autosomal dominant (ADAD), early onset (EOAD) and late onset (LOAD). Ultimately, AD is characterized by the deposition of Aβ and ptau protein aggregates in the brain. This work aims to identify and characterize common disrupted pathways across AD etiologies.METHODWe examined bulk transcriptomic data from brain donors to the DIAN (ADAD, N=19) and Knight-ADRC (EOAD, N=13; LOAD, N=55; controls, N=16). We performed differential gene expression (DGE) analyses using DSeq2 and cross-checked significant signals with known GWAs loci. We replicated our findings in three AMP-AD independent studies.RESULTDGE analysis identified 57 significantly differentiated genes across ADAD, EOAD or LOAD vs controls. Among those, AGFG2 (p=7×10^-4 ) had a higher expression in cases and falls under the AD GWAs signal for NYAP1 (rs1476679). This effect replicated in all independent datasets: Mount Sinai (p=8.63×10^-3 ), Mayo (p=5.88×10^-12 ), ROSMAP (p=3.96×10^-05 ). AGFG2 is expressed primarily in astrocytes and is a member of the HIV-1 Rev binding protein family that mediates the nucleocytoplasmic transfer of proteins and RNAs. AGFG2 has been implicated in APP metabolism, leading to the hypothesis that higher expression of AGFG2 could promote more release of APP to the media.CONCLUSIONOur results suggest that AGFG2 may be a novel player in the etiology of AD. We are currently modifying AGFG2 expression on iPSC-derived astrocytes using CRIPR-Cas9 technology to evaluate AGFG2 role in APP and Tau metabolism. We will present these results at the conference.

项与 NYAP1 相关的新闻（医药）

2023-05-09

·生物制品圈

最新！南加州大学发现肝癌治疗新靶点！

导读：肝细胞癌(HCC)是最致命的第三大恶性肿瘤。肝癌中激活的肝星状细胞(aHSC)与癌症相关的成纤维细胞被认为是一个潜在的治疗靶点。5月8日，南加州大学研究人员在《Nature：Communications》上发表了名为“Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis”的文章，研究人员称发现了新的肝癌治疗靶点。https://www.nature.com/articles/s41467-023-38406-8研究背景 01 肝细胞癌(HCC)是第三大最致命的恶性肿瘤。肝细胞癌中激活的肝星状细胞(aHSC)在与癌症相关的成纤维细胞，被认为是一个潜在的治疗靶点。研究人员报道了Scd2（一种饱和酶）在肝星状细胞中抑制肿瘤和肿瘤微环境，并防止雄性小鼠患上肝脏肿瘤。细活化的肝星状细胞(aHSC)促进HCC成为癌症相关成纤维细胞(CAF)。代谢性肝病（如酒精性和非酒精性脂肪性肝炎）目前被认为是肝细胞癌的主要易感因素，取代了病毒性肝炎。然而，在这种情况下，aHSC-HCC串扰在HCC发展中的具体性质尚不清楚。研究方法 02研究人员首先验证了小鼠在肝星状细胞中选择性消融Scd2的作用。为此他们对小鼠肝细胞进行了单细胞RNA测序(scRNA-seq)。该分析确定了表达其标记基因的不同细胞类型的簇。其中，Scd2在内皮细胞、巨噬细胞、门静脉成纤维细胞(PF)、树突状细胞中表达。接下来，我们通过对肝肿瘤邻近组织的RNA测序探讨了aHSC、SCD2缺乏抗肿瘤作用的机制。研究人员认为这些被称为肿瘤邻近肝(TAL)的组织是研究肝星状细胞-肿瘤细胞串扰的理想组织，因为它们在显微镜下，尽管肿瘤并不明显。差异表达基因(DEGs)的热图描绘了不同转录组学景观(图1a)。Yap1的转录受到CTNNB112的正调控，Yap1和CTNNB1同时受到抑制，表示Yap1的抑制可能是由CTNNB1的减少引起的。研究人员还想知道这种调节是肝脏肿瘤发生所特有的，还是也与正常肝脏有关。为此分析了小鼠肝脏中主要在肝细胞和胆管细胞中缺乏CTNNB1的YAP1和Scd1/2的表达。IB分析显示肝脏中YAP1、TAZ、HuR和LRP6下调。CTNNB113和Yap1/ Wwtr1 mRNA的预期靶点Scd1/2也受到抑制。这表明即使在正常肝细胞中，CTNNB1也能正向调节Yap1/ TAZ和SCD-HuR-LRP6通路。SCD2是产生mufa所必需的酶，mufa通过延伸和去饱和产生多不饱和脂肪酸(PUFA)。因此，研究人员对Scd2f/f CC与Scd2f/f肝脏中的PUFA代谢物进行了脂质组学分析。为验证LTB4R2在HCC中的作用，研究人员检测了LTB4R2的药理学和遗传学抑制对人HCC细胞株Huh7生长的影响。LTB4R2拮抗剂LY255283的浓度抑制Huh7的生长。shRNA对LTB4R2的表达使其减少80%，但对LTB4R1 mRNA没有影响，证实了LTB4R2的促生长作用。LTB4R2 KD降低了nYAP1和CTNNB1。LTB4R2在2000年被发现为LTB4的低亲和力受体，随后12-HHTrE被鉴定为高亲和力LTB4R2配体。研究描述了LTB4R2通过激活CTNNB1和YAP1在肝脏肿瘤发展中的作用，CTNNB1和YAP1是两种促进肝脏肿瘤发生的转录激活因子。研究人员的scRNA-seq分析发现，Lrat+Fbln2+ aHSC亚群是CYP1B1催化的12-HHTrE生成的假定来源。scd2依赖性Cyp1b1上调的机制目前尚不清楚，但可能涉及CTNNB1-AhR对Cyp1a134的转录激活。TCGA-LIHC队列分析未能显示LTB4R2表达与不良生存率之间的正相关。研究人员发现的LTB4R2通路可能仅在肝癌生长的病灶区域有活性，并且可能无法通过RNA-seq准确评估。事实上对小鼠的RNA-seq分析未能检测到Ltb4r2表达降低，尽管IB或qPCR显著减少。TME中表达cyp1b1的aHSC群体相对较少。因此，只有那些被CYP1B1+ aHSC包围的HCC细胞才能表达LTB4R2——这是CYPB1-LTB4R2通路独特的局灶性和空间性。https://www.nature.com/articles/s41467-023-38406-8研究意义 03肝星状细胞（aHSC）依赖于SCD和CYP1B1的方式释放12-HHTrE，其条件培养基在HCC细胞中再现了ltb4r2介导的12-HHTrE促进肿瘤生长的作用。总之，研究结果表明肝星状细胞启动的12-hhtrer-ltb4r2-ctnnb1-yap1通路是潜在的肝细胞癌治疗靶点。参考资料：https://www.nature.com/articles/s41467-023-38406-8

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