Exploring Disrupted H3K27me3 in Mendelian Disorders of the Epigenetic Machinery and Restoring Its Balance as a Therapeutic Approach to Treat Abnormal Growth

探索表观遗传机制孟德尔紊乱中 H3K27me3 的破坏并恢复其平衡作为治疗异常生长的治疗方法

• 批准号: 10878445
• 负责人: Jill A Fahrner
• 金额: $ 9.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10878445
• 关键词: Advisory Committees; Authorization documentation; Biological Markers; Biology; CXCL14 gene; Cells; ChIP-seq; Child; Child Health; Chondrocytes; Chromatin; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Constitution; Constitutional; DNA Sequence Alteration; Data; Defect; Development; Development Plans; Disease; EZH2 gene; Epigenetic Process; Epiphysial cartilage; Equilibrium; Exhibits; Face; Gene Expression; Genes; Genetic Medicine; Goals; Growth; Heterozygote; Histologic; Histones; Human; Individual; Intellectual functioning disability; Kabuki Make-Up Syndrome; Knock-in Mouse; Laboratories; Malignant Neoplasms; Mendelian disorder; Mentored Clinical Scientist Development Award (K08); Mentors; Molecular; Molecular Abnormality; Mus; Mutant Strains Mice; Mutate; Neurologic; Outcome Measure; Pathogenesis; Patients; Phenotype; Physiologic Ossification; Positioning Attribute; Productivity; Qualifying; Rare Diseases; Recurrence; Research; Research Personnel; Resolution; Role; SET Domain; Therapeutic; Therapeutic Effect; Therapeutic Trials; Weaver Syndrome; Work; Writing; authority; bone; career; career development; cell type; effective therapy; epigenetic therapy; genome-wide; histone methyltransferase; inhibitor; innovation; long bone; microCT; mouse model; new therapeutic target; novel; prevent; promoter; skeletal; skills; supportive environment; transcriptomic profiling; treatment strategy

Project summary/Abstract:Growth and neurologic development are fundamental aspects of child health. Both are consistently disrupted in Mendelian disorders of the epigenetic machinery (MDEMs), an emerging group of conditions resulting from genetic mutations in components of the epigenetic machinery. Though individually rare, this group of disorders accounts for a striking 19% of intellectual disability (ID). The percentage of growth abnormalities attributable to MDEMs is unknown, though estimates suggest 2-5 million U.S. children exhibit abnormal growth, and it is the second most common manifestation of MDEMs seen in our novel Epigenetics and Chromatin Clinic. Abnormalities of growth can manifest as growth retardation or overgrowth; either can be devastating. No consistently effective treatments exist. We recently proposed the Balance Hypothesis to explain the molecular pathogenesis of MDEMs, suggesting that a delicate balance exists between components of the epigenetic machinery (and closed and open chromatin states) at individual target genes and that perturbation of this balance with a MDEM would be expected to alter target gene expression. Previous work from our laboratory supports this idea and suggests that a subset of ID may be treatable, raising the question of whether abnormal growth also may be treatable. Two MDEMs, Kabuki syndrome 2 (KS2) and Weaver Syndrome (WS), are characterized by opposing growth abnormalities, with KS2 exhibiting growth retardation and WS exhibiting overgrowth. Their molecular defects converge on the same histone mark, H3K27me3, and disrupt it in opposite directions. We have elucidated a robust skeletal growth retardation phenotype and have identified a relevant cell type in KS2, and we have created a novel mouse model of WS. This proposal aims to use a comparison of two disorders with opposing growth phenotypes and disruptions of H3K27me3 to understand the role of this mark in abnormal growth, establish H3K27me3 as a biomarker of disease and therapeutic effect, and develop therapeutic strategies to influence this mark to treat abnormal growth. H3K27me3 is disrupted in diverse disease states involving abnormal growth. Thus targeting it has broad applicability, and identifying treatable forms of abnormal growth could help children across the U.S. A K08 Mentored Clinical Scientist Development Award will help me to not only potentially impact children's' lives, but also achieve my career goals of becoming an independent investigator and a national authority on translational epigenetics. These are achievable goals in the rigorous yet supportive environment in the Johns Hopkins Institute of Genetic Medicine with the skills I expect to gain from my rigorous career development plan and with the support anticipated from my superb mentors and advisory committees, which include world-renowned authorities on epigenetic disease and bone biology. Moreover, I am uniquely qualified to pursue this work because I have a long-standing, productive background in epigenetics, and my clinical activities in the novel Epigenetics and Chromatin Clinic focus on the disorders I study in the lab and will thus inform my research.

项目概要/摘要：生长和神经发育是儿童健康的基本方面。两 在孟德尔表观遗传机制障碍（MDEM）中持续受到破坏，这是一组新兴的 由表观遗传机制组成部分的基因突变引起的疾病。虽然个别 虽然罕见，但这组疾病占智力残疾（ID）的19%。增长的百分比 归因于MDEMs的异常尚不清楚，尽管估计有200 - 500万美国儿童表现出 异常生长，这是第二个最常见的表现MDEMs看到我们的小说表观遗传学 染色质诊所生长发育障碍可以表现为生长迟缓或过度生长;两者都可以是 毁灭性的没有持续有效的治疗方法。我们最近提出了平衡假说， 解释MDEMs的分子发病机制，表明成分之间存在微妙的平衡 表观遗传机制（和封闭和开放的染色质状态）在个别靶基因， 用MDEM扰乱这种平衡将预期改变靶基因表达。以前的工作 来自我们实验室的研究支持了这一观点，并表明ID的一个子集可能是可以治疗的，这就提出了一个问题， 异常生长是否也可以治疗。两个MDEM，歌舞伎综合征2（KS 2）和韦弗 综合征（WS）的特征在于相反的生长异常，其中KS 2表现出生长迟缓 而WS表现出过度生长。它们的分子缺陷集中在相同的组蛋白标记H3 K27 me 3上， 把它从相反的方向打乱。我们已经阐明了一个强大的骨骼生长迟缓表型， 在KS 2中鉴定了相关细胞类型，并且我们创建了一种新型WS小鼠模型。该提案旨在 使用具有相反生长表型和H3 K27 me 3破坏的两种疾病的比较， 了解这种标记在异常生长中的作用，将H3 K27 me 3确立为疾病的生物标志物， 治疗效果，并开发治疗策略来影响该标记以治疗异常生长。 H3 K27 me 3在涉及异常生长的多种疾病状态中被破坏。因此，瞄准它具有广泛的 适用性，并确定可治疗的形式的异常生长可以帮助儿童在美国。 指导临床科学家发展奖将帮助我不仅潜在地影响儿童的生活， 我也实现了我的职业目标，成为一名独立的调查员和国家翻译权威 表观遗传学这些都是在约翰霍普金斯严格但支持的环境中可以实现的目标 遗传医学研究所的技能，我希望从我严格的职业发展计划中获得， 我期望得到我的优秀导师和咨询委员会的支持，其中包括世界知名的 表观遗传疾病和骨骼生物学的权威。而且，我是唯一有资格从事这项工作的人 因为我在表观遗传学方面有着长期的、富有成效的背景，我在小说中的临床活动 表观遗传学和染色质诊所专注于我在实验室研究的疾病，因此将为我的研究提供信息。