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: 10569853
• 负责人: Jill A Fahrner
• 金额: $ 2.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569853
• 关键词: Advisory Committees; Biological Markers; Biology; Child; Child Health; Chromatin; Clinic; Clinical; DNA Sequence Alteration; Defect; Development; Development Plans; Disease; Epigenetic Process; Equilibrium; Exhibits; Gene Expression; Genes; Genetic Medicine; Goals; Growth; Histones; Individual; Institutes; Intellectual functioning disability; Kabuki Make-Up Syndrome; Laboratories; Mendelian disorder; Mentored Clinical Scientist Development Award (K08); Mentors; Molecular; Neurologic; Pathogenesis; Phenotype; Rare Diseases; Research; Research Personnel; Role; Therapeutic; Therapeutic Effect; Weaver Syndrome; Work; authority; bone; career; career development; cell type; effective therapy; mouse model; new therapeutic target; novel; skeletal; skills; supportive environment; treatment strategy

Project Summary 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 成长和神经系统发展是儿童健康的基本方面。两者都始终受到干扰 表观遗传机械（MDEMS）的孟德尔疾病，这是一组新兴的疾病。 表观遗传机械组成部分中的基因突变。尽管个别罕见，但这组疾病 罢工占智力残疾的19％（ID）。增长异常的百分比归因于 MDEM是未知的，尽管估计表明2-5万美国儿童暴露了异常增长，这是 在我们的新型表观遗传学和染色质诊所中看到的第二个最常见的MDEM表现。 生长异常可能表现为生长迟缓或过度生长。两者都可能是毁灭性的。不 始终存在有效的治疗方法。我们最近提出了平衡假设来解释分子 MDEM的发病机理，表明表观遗传学的成分之间存在微妙的平衡 在单个靶基因处的机械（以及封闭和开放的染色质状态），并且这种扰动 与MDEM保持平衡将有望改变靶基因表达。我们实验室的先前工作 支持这个想法，并暗示ID的子集可能是可以治疗的，这提出了一个问题，即是否异常 增长也可以治疗。两个MDEM，Kabuki综合征2（KS2）和Weaver综合征（WS），为 具有相反生长异常的特征，KS2表现出生长迟缓和WS表现 过度生长。它们的分子缺陷会在同一组蛋白标记H3K27me3上收敛，并在相反 方向。我们已经阐明了稳健的骨骼生长延迟表型，并确定了相关的 KS2中的细胞类型，我们创建了WS的新型鼠标模型。该建议旨在使用 两种疾病具有相反的生长表型和H3K27me3的破坏，以了解这一点的作用 标记异常生长，将H3K27me3建立为疾病和治疗效应的生物标志物，并发展 影响这种商标以治疗异常生长的治疗策略。 H3K27me3在潜水员中被破坏 涉及异常生长的疾病状态。该目标具有广泛的适用性，并确定可治疗的 异常增长的形式可以帮助美国的儿童K08指导的临床科学家发展 奖项将不仅可以帮助我影响儿童的生活，还可以实现我的职业目标 成为独立研究者和翻译表观遗传学的国家权威。这些都是 约翰·霍普金斯遗传医学研究所的严格但支持环境中的可实现目标 我希望从严格的职业发展计划中获得的技能，并在预期的支持下获得 我的出色导师和咨询委员会包括世界知名的表观遗传疾病的当局 和骨生物学。此外，我很有资格从事这项工作，因为我有一个长期的， 表观遗传学的生产背景以及我在新型表观遗传学和染色质诊所中的临床活动 专注于我在实验室学习的疾病，从而为我的研究提供信息。