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.

项目概要 生长和神经发育是儿童健康的基本方面，两者始终受到干扰。 表观遗传机制孟德尔紊乱 (MDEM) 是一组由以下原因引起的新兴疾病 表观遗传机制中的基因突变虽然个别罕见，但这一组疾病。 导致智力障碍 (ID) 的比例高达 19%。 MDEM 尚不清楚，但估计有 2-500 万美国儿童表现出异常生长，这是 在我们的新型表观遗传学和染色质诊所中观察到的 MDEM 的第二常见表现。 生长异常可以表现为生长迟缓或过度生长；两者都可能是毁灭性的。 我们最近提出了平衡假说来解释分子机制。 MDEM 的发病机制，表明表观遗传成分之间存在微妙的平衡 单个靶基因的机制（以及封闭和开放的染色质状态）以及该机制的扰动 与 MDEM 的平衡预计会改变我们实验室之前的工作。 支持这一观点，并建议智力障碍的一部分是可以治疗的，从而提出了是否异常的问题 两种 MDEM：歌舞伎综合征 2 (KS2) 和韦弗综合征 (WS) 也是可以治疗的。 其特点是相反的生长异常，KS2 表现出生长迟缓，WS 表现出 它们的分子缺陷集中在相同的组蛋白标记 H3K27me3 上，并以相反的方式破坏它。 我们已经阐明了强健的骨骼生长迟缓表型，并确定了相关的相关方向。 KS2 中的细胞类型，并且我们创建了一种新的 WS 小鼠模型。该提案旨在使用 WS 的比较。 两种具有相反生长表型和 H3K27me3 破坏的疾病，以了解其作用 标记异常生长，将H3K27me3建立为疾病和治疗效果的生物标志物，并开发 影响该标记以治疗 H3K27me3 异常生长的治疗策略有多种。 因此，针对涉及异常生长的疾病状态具有广泛的适用性，并确定可治疗的方法。 各种形式的异常生长可以帮助美国各地的儿童 K08 指导临床科学家发展 该奖项不仅能帮助我影响孩子们的生活，还能帮助我实现我的职业目标： 成为转化表观遗传学的独立研究者和国家权威。 在约翰霍普金斯大学遗传医学研究所严格但支持性的环境中可实现的目标 凭借我期望从严格的职业发展计划中获得的技能以及预期的支持 我出色的导师和咨询委员会，其中包括表观遗传疾病领域的世界知名权威 此外，我有独特的资格从事这项工作，因为我有长期的、 表观遗传学的丰富背景，以及我在新型表观遗传学和染色质诊所的临床活动 专注于我在实验室研究的疾病，从而为我的研究提供信息。