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: 10251023
• 负责人: Jill A Fahrner
• 金额: $ 16.94万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251023
• 关键词: Advisory Committees; Biological Markers; Biology; CXCL14 gene; Cells; ChIP-seq; Child; Child Health; Chondrocytes; Chromatin; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; 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; Histologic; Histones; Human; Individual; Institutes; 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; Rare Diseases; Recurrence; Research; Research Personnel; Resolution; Role; SET Domain; Therapeutic; Therapeutic Effect; Therapeutic Trials; Weaver Syndrome; Work; Writing; authority; base; bone; career; career development; cell type; effective therapy; epigenetic therapy; genome-wide; histone methyltransferase; inhibitor/antagonist; innovation; long bone; microCT; mouse model; new therapeutic target; novel; prevent; promoter; skeletal; skills; supportive environment; transcriptome; 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.

项目摘要/摘要：生长和神经发育是儿童健康的基本方面。两个都 孟德尔表观遗传机制紊乱 (MDEM) 一直受到破坏，这是一个新兴的群体 由表观遗传机制的组成部分的基因突变引起的疾病。虽然单独 罕见的是，这组疾病占智力障碍 (ID) 的 19%。增长百分比 MDEM 导致的异常情况尚不清楚，但估计有 2-500 万美国儿童出现异常 生长异常，这是我们的小说表观遗传学中第二常见的 MDEM 表现 和染色质诊所。生长异常可表现为生长迟缓或过度生长；两者都可以 毁灭性的。不存在持续有效的治疗方法。我们最近提出了平衡假说 解释 MDEM 的分子发病机制，表明各成分之间存在微妙的平衡 单个靶基因的表观遗传机制（以及封闭和开放染色质状态） 用 MDEM 扰乱这种平衡预计会改变靶基因的表达。以前的工作 我们实验室的研究人员支持这一观点，并提出智力障碍的一部分是可以治疗的，从而提出了以下问题： 异常生长是否也可以治疗。两种 MDEM，歌舞伎综合症 2 (KS2) 和 Weaver 综合征 (WS)，其特征是相反的生长异常，其中 KS2 表现出生长迟缓 和 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 H3K27me3 上，并且 以相反的方向扰乱它。我们已经阐明了一种强大的骨骼生长迟缓表型，并且已经 在 KS2 中鉴定出一种相关的细胞类型，并且我们创建了一种新型 WS 小鼠模型。该提案旨在 通过比较具有相反生长表型和 H3K27me3 破坏的两种疾病来 了解该标记在异常生长中的作用，建立 H3K27me3 作为疾病的生物标记，以及 治疗效果，并制定治疗策略来影响该标记以治疗异常生长。 H3K27me3 在涉及异常生长的多种疾病状态下受到破坏。因此它的目标具有广泛的 适用性并确定可治疗的异常生长形式可以帮助美国各地的儿童 A K08 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，而且 也实现了我的职业目标，成为一名独立研究者和国家转化权威 表观遗传学。在约翰·霍普金斯大学严格但支持性的环境中，这些目标是可以实现的 遗传医学研究所拥有我希望从严格的职业发展计划中获得的技能以及 我的卓越导师和咨询委员会（其中包括世界知名人士）的预期支持 表观遗传疾病和骨生物学方面的权威。此外，我具有独特的资格来从事这项工作 因为我在表观遗传学方面拥有长期、富有成效的背景，并且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，从而为我的研究提供信息。