Therapeutic potential for Prader-Willi syndrome

普瑞德威利综合征的治疗潜力

• 批准号: 8860216
• 负责人: YONG-HUI JIANG
• 金额: $ 22.46万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860216
• 关键词: Affect; Angelman Syndrome; Binding; Candidate Disease Gene; Cells; Chimeric Proteins; Chromosomes; Clinical; Collaborations; CpG Islands; Cultured Cells; DNA; DNA Methylation; Data; Defect; Development; Developmental Delay Disorders; Embryo; Epigenetic Process; FDA approved; Fibroblasts; Gene Expression; Genes; Genetic Transcription; Genomic Imprinting; Goals; Health; Hereditary Disease; Histones; Human; Hyperphagia; Hypogonadism; Individual; Lead; Lysine; Measures; Methodology; Modification; Molecular; Molecular Target; Mus; Mutant Strains Mice; National Institute of Mental Health; North Carolina; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Prader-Willi Syndrome; Preclinical Drug Evaluation; Process; Psychotropic Drugs; Quality of life; Reporting; Repression; SNRPN; Small Nucleolar RNA; Specificity; Testing; Therapeutic; Therapeutic Intervention; Transcript; Universities; Untranslated RNA; Work; chromatin modification; cytotoxicity; disability; dosage; drug candidate; embryonic stem cell; genome-wide; histone methyltransferase; histone modification; imprint; in vivo; inhibitor/antagonist; innovation; insight; interest; mouse model; neurobehavioral disorder; novel; obesity in children; programs; promoter; response; screening; small molecule; small molecule libraries; tool

DESCRIPTION (provided by applicant): Like most genetic disorders, no specific therapeutic intervention targets the specific molecular defect of Prader- Willi syndrome (PWS), a genomic imprinting and neurobehavioral disorder. PWS is caused by paternal deficiency of genes in the chromosome 15q11-q13 region. The corresponding genes in the maternal chromosome are structurally intact, but their transcription is repressed epigenetically. The involvement of epigenetic repression renders PWS as one of the best opportunities to explore molecular therapy. Recent reports indicate SnoRNA, clusters including HBII-85 (SNORD116) between the SNRPN and UBE3A genes, is responsible for key features of PWS including childhood obesity, hypogonadism, hyperphagia, and developmental delay. Epigenetic mechanisms, including DNA methylation and chromatin modifications at the PWS imprinting center region (PWS-ICR), are involved in regulating the paternal-specific expression of genes including SNRPN and SnoRNAs in the 15q11-q13 region. The imprinting domain in the 15q11-q13 region is highly conserved in mice. The expression of SnoRNA clusters is processed from continuous transcripts initiated from the PWS-ICR/promoter bound CpG island of SNRPN. DNA methylation can activate the expression of the SNRPN gene from the silent maternal chromosome in cultured cells of PWS patients and mouse models, but its clinical utility is limited by the concern of the genome wide effect of these drugs. These observations, however, strongly support a approach to unsilence/activate the expression of SnoRNAs from maternal chromosome through an epigenetic mechanism. Because the SnoRNAs are non-coding, we propose to use embryonic fibroblasts (MEFs) from mice carrying Snrpn-EGFP fusion protein as screening tool. Drugs that activate the Snrpn-EGFP are expected to have the same impact on the SnoRNAs. In collaboration with Dr. Bryan Roth (Director of NIMH Psychoactive Drug Screening Program), we have completed the first phase screen and identified several candidate drugs. We have showed that a histone methyltransferase inhibitor activated the expression of Snrpn and SnoRNAs from the maternal chromosome in cultured PWS cells. Using the same strategy, Dr. Roth's team also identified a FDA approved drug that activates the Angelman syndrome Ube3a gene from paternal chromosome in vivo. The long term goal of our project is to develop a therapeutic intervention targeted to the specific epigenetic defects of PWS. The central hypothesis is that a small molecule can modulate the epigenetic modification in the PWS-ICR and lead to the activation of the silenced PWS candidate genes from the maternal chromosome. The specific objective is to identify and characterize small molecules that activate the expression of Snrpn and SnoRNAs from the maternal chromosome by performing high-content small molecule screening using maternal Snrpn-EGFP as a marker. The proposed study is significant because it will lead to the development of a therapeutic intervention in PWS and provide the novel insight for molecular mechanism underlying the genomic imprinting.

描述（由申请人提供）：像大多数遗传疾病一样，没有特定的治疗干预针对Prader- Willi综合征（PWS）的特定分子缺陷，PWS是一种基因组印记和神经行为障碍。PWS是由染色体15q11-q13区域父本基因缺失引起的。母体染色体中相应的基因在结构上是完整的，但其转录在表观遗传上受到抑制。表观遗传抑制的参与使PWS成为探索分子治疗的最佳机会之一。最近的报道表明，SNRPN和UBE3A基因之间的包括HBII-85 （SNORD116）在内的簇状SnoRNA负责PWS的关键特征，包括儿童肥胖、性腺功能减退、贪食和发育迟缓。表观遗传机制，包括PWS印记中心区域（PWS- icr）的DNA甲基化和染色质修饰，参与调节15q11-q13区域SNRPN和SnoRNAs等基因的父本特异性表达。15q11-q13区域的印迹结构域在小鼠中是高度保守的。SNRPN的PWS-ICR/启动子结合CpG岛启动的连续转录本处理了SnoRNA簇的表达。在PWS患者和小鼠模型的培养细胞中，DNA甲基化可以激活来自沉默母体染色体的SNRPN基因的表达，但由于担心这些药物的全基因组效应，其临床应用受到限制。然而，这些观察结果有力地支持了一种通过表观遗传机制解除沉默/激活母体染色体上snorna表达的方法。由于snorna是非编码的，我们建议使用携带Snrpn-EGFP融合蛋白的小鼠胚胎成纤维细胞（mef）作为筛选工具。激活Snrpn-EGFP的药物有望对snorna产生同样的影响。在与Bryan Roth博士（NIMH精神活性药物筛选项目主任）的合作下，我们已经完成了第一阶段的筛选，并确定了几种候选药物。我们发现，在培养的PWS细胞中，一种组蛋白甲基转移酶抑制剂激活了母体染色体中Snrpn和snorna的表达。采用同样的策略，罗斯博士的团队还发现了一种FDA批准的药物，可以在体内激活来自父亲染色体的天使综合征Ube3a基因。我们项目的长期目标是开发针对PWS特定表观遗传缺陷的治疗干预措施。核心假设是，一个小分子可以调节PWS- icr的表观遗传修饰，并导致来自母体染色体的沉默PWS候选基因的激活。具体目的是通过使用母体Snrpn- egfp作为标记进行高含量小分子筛选，鉴定和表征激活来自母体染色体的Snrpn和snorna表达的小分子。这项研究具有重要意义，因为它将导致PWS治疗干预的发展，并为基因组印记的分子机制提供新的见解。

项目成果

Psychometric properties of the Chinese Parent Version of the Autism Spectrum Rating Scale: Rasch analysis.

• DOI: 10.1177/13623613211004054
• 发表时间: 2021-10
• 期刊: Autism : the international journal of research and practice
• 作者: Yan W;Siegert RJ;Zhou H;Zou X;Wu L;Luo X;Li T;Huang Y;Guan H;Chen X;Mao M;Xia K;Zhang L;Li E;Li C;Zhang X;Zhou Y;Shih A;Fombonne E;Zheng Y;Han J;Sun Z;Jiang YH;Wang Y
• 通讯作者: Wang Y

Potassium channel dysfunction in human neuronal models of Angelman syndrome.

• DOI: 10.1126/science.aav5386
• 发表时间: 2019-12-20
• 期刊: Science (New York, N.Y.)
• 作者: Sun AX;Yuan Q;Fukuda M;Yu W;Yan H;Lim GGY;Nai MH;D'Agostino GA;Tran HD;Itahana Y;Wang D;Lokman H;Itahana K;Lim SWL;Tang J;Chang YY;Zhang M;Cook SA;Rackham OJL;Lim CT;Tan EK;Ng HH;Lim KL;Jiang YH;Je HS
• 通讯作者: Je HS

Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge.

染色体微阵列分析在神经发育障碍临床评估中的应用——报告SETDB1的新缺失并说明咨询挑战

• DOI: 10.1038/pr.2016.101
• 发表时间: 2016-09
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Xu Q;Goldstein J;Wang P;Gadi IK;Labreche H;Rehder C;Wang WP;McConkie A;Xu X;Jiang YH
• 通讯作者: Jiang YH

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.

• DOI: 10.1038/nm.4257
• 发表时间: 2017-03
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Kim Y;Lee HM;Xiong Y;Sciaky N;Hulbert SW;Cao X;Everitt JI;Jin J;Roth BL;Jiang YH
• 通讯作者: Jiang YH

Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links.

• DOI: 10.1016/j.neuroscience.2015.12.040
• 发表时间: 2016-05-03
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Hulbert SW;Jiang YH
• 通讯作者: Jiang YH