Enabling temporal and spatial restriction of MYT1L to identify molecular and postnatal circuit-level druggable targets

启用 MYT1L 的时间和空间限制来识别分子和出生后电路级可药物靶标

• 批准号: 10727978
• 负责人: Susan Eileen Maloney
• 金额: $ 15.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10727978
• 关键词: Address; Adult; Anxiety; Area; Attention deficit hyperactivity disorder; Base Pairing; Behavior; Behavioral; Brain; Cells; Chromatin; Clinical; Detection; Development; Developmental Delay Disorders; Diagnosis; Disease; Embryo; Embryonic Development; Enterobacteria phage P1 Cre recombinase; Epilepsy; Excision; Exons; Failure; Frameshift Mutation; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Human; Hyperactivity; Intellectual functioning disability; Knockout Mice; Language; Language Development; Lead; Memory impairment; Microcephaly; Modeling; Molecular; Molecular Target; Motor; Muscle hypotonia; Mutation; Neonatal; Neuronal Differentiation; Neurosecretory Systems; Obesity; Pathway interactions; Patients; Penetrance; Phenotype; Pre-Clinical Model; Prevalence; Proteins; Rare Diseases; Reagent; Role; Social Behavior; Symptoms; Syndrome; Therapeutic; Thinness; Time; Weight Gain; Work; autism spectrum disorder; cell type; clinical phenotype; clinically relevant; conditional knockout; design; developmental disease; druggable target; human disease; indexing; inducible Cre; insight; loss of function mutation; mouse model; neurobiological mechanism; neurodevelopment; neuropsychiatry; new therapeutic target; novel; postnatal; protein function; social; stereotypy; targeted treatment; therapeutic target; tool; transcription factor; white matter

Project Summary Putative loss of function mutations in the MTY1L gene lead to a newly defined intellectual and developmental syndrome, yet the neurobiological mechanisms underlying this relationship remain unknown. MYT1L Syndrome is characterized by global developmental delay (particularly in motor and language development), intellectual disability, highly penetrant obesity and hypotonia, and a significant subset with autism spectrum disorder and/or attention-deficit/hyperactivity disorder. Other symptoms of variable penetrance include epilepsy, microcephaly, white-matter thinning, and neuroendocrine disruptions. Thus far, about 100 patients have been described clinically and prevalence estimates are ~1:2000. However, the function of MYT1L has just begun to be studied, therefore, we currently know very little about how MYT1L loss of function mutations result in disease. We recently developed the first MYT1L haploinsufficient mouse model, which successfully recapitulated many of the patient phenotypes, including hyperactivity, changes in communicative behavior, social behavior challenges, muscle hypotonia, microcephaly, and obesity. We also identified disrupted gene expression, precocious neuronal differentiation as a mechanism for microcephaly, and failure of transcriptional and chromatin maturation in adults. Thus, with this model, we enhanced the understanding of MYT1L function and established a preclinical model of MYT1L Syndrome. However, it is unknown when during development, and where in the brain the disruption of MYT1L protein leads to each specific clinically-relevant phenotype. This is because we lack the ability to clearly define the relevant molecular and circuit-level targets of MYT1L, identification of which would enable studies of potential rescue therapies. To begin to address these holes, we recently generated a MYT1L conditional model targeting the same exon as our constitutive haploinsufficient model to allow for spatial and temporal restriction of MYT1L loss. The goal of this project is to validate this tool for temporal and spatial applications, and to determine the extent to which postnatal MYT1L function is responsible for the phenotypes observed in adults and identify the genes regulated by MYT1L in the postnatal brain. Such insights will serve to help define druggable molecular and circuit targets, as well as therapeutic temporal windows for MYT1L syndrome. In Aim 1, we will validate our new tool for inducing MYT1L loss in a temporally and spatially controlled manner and for enabling studies of molecular targets for potential therapeutic action. A fundamental question we must answer to develop therapeutic strategies for this rare disease is if MYT1L loss disrupts neurodevelopment (i.e, in the embryo) or neuromaintenance (i.e., postnatally, and in adults). In order to address this question, in Aim 2, we will leverage our new conditional model and inducible Cre-recombinase genetic tools to induce loss of MYT1L in the postnatal brain, after completion of early neurodevelopment, and determine which phenotypes are due to the postnatal functions of MYT1L. Ultimately, this tool will guide future studies into targeted therapies for MYT1L Syndrome, and potentially other related IDDs.

项目摘要 MTY 1 L基因中假定的功能缺失突变导致新定义的智力和发育障碍 综合征，但这种关系的神经生物学机制仍然未知。MYT 1 L综合征 其特征是整体发育迟缓（特别是在运动和语言发育），智力 残疾、高度外显性肥胖和肌张力减退，以及自闭症谱系障碍和/或 注意力缺陷多动症其他症状包括癫痫，小头畸形， 白质变薄和神经内分泌紊乱到目前为止，大约有100名患者被描述为 临床和患病率估计值约为1：2000。然而，MYT 1 L的功能才刚刚开始研究， 因此，我们目前对MYT 1 L功能缺失突变如何导致疾病知之甚少。我们最近 开发了第一个MYT 1 L单倍不足的小鼠模型，该模型成功地重现了许多患者 表型，包括多动，交流行为的变化，社会行为的挑战，肌肉 张力减退、小头畸形和肥胖。我们还发现了基因表达的破坏， 分化作为小头畸形的机制，以及成年人转录和染色质成熟的失败。 因此，通过该模型，我们加深了对MYT 1 L功能的理解，并建立了临床前模型 MYT 1 L综合征然而，目前还不清楚在发育过程中何时，以及大脑中的何处中断， MYT 1 L蛋白的表达导致每种特定的临床相关表型。这是因为我们缺乏能力， 明确定义MYT 1 L的相关分子和电路水平靶点， 研究潜在的补救疗法。为了开始解决这些漏洞，我们最近生成了一个MYT 1 L 条件模型靶向与我们的组成型单倍体模型相同的外显子， MYT 1 L缺失的时间限制。这个项目的目标是验证这个工具的时间和空间 应用，并确定出生后MYT 1 L功能在多大程度上负责表型 在成年人中观察，并确定出生后大脑中MYT 1 L调控的基因。这些见解将有助于 帮助确定可药物化的分子和回路靶点，以及MYT 1 L的治疗时间窗 综合征在目标1中，我们将验证我们的新工具，用于在时间和空间控制下诱导MYT 1 L损失。 的方式，并使潜在的治疗作用的分子靶点的研究。一根本性的问题 我们必须回答的是，如果MYT 1 L缺失破坏了这种罕见疾病的治疗策略， 神经发育（即，在胚胎中）或神经维持（即，在成年人和成年人中）。为了解决 在目标2中，我们将利用我们新的条件模型和诱导型Cre重组酶遗传工具 在完成早期神经发育后，诱导出生后大脑中MYT 1 L的丢失，并确定 表型是由于MYT 1 L的出生后功能。最终，该工具将指导未来的研究， MYT 1 L综合征的靶向治疗，以及潜在的其他相关IDDs。