Investigating the role of Growth-differentiation factor 11 in neurodevelopmental and MECP2-related disorders

研究生长分化因子 11 在神经发育和 MECP2 相关疾病中的作用

基本信息

批准号：
10405275
负责人：
Sameer Bajikar
金额：
$ 3.52万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2022-03-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405275
关键词：
Acute Address Alleles Anxiety Behavior Binding Proteins Brain Brain region Brain-Derived Neurotrophic Factor Catalogs Computer Models DNA Data Set Defect Dendrites Development Developmental Delay Disorders Disease Dose Family Fellowship GDF11 gene Gene Expression Genes Genetic Goals Growth Factor Human IGF1 gene Individual Intellectual functioning disability Knock-out Knockout Mice Language Lead Learning Ligands Live Birth MeCP2 Duplication Syndrome Memory Meta-Analysis Methods Methyl-CpG-Binding Protein 2 Modeling Molecular Morphology Motor Mus Mutation Neurodevelopmental Disorder Neurologic Neuronal Dysfunction Neurophysiology - biologic function Nuclear Protein Pathogenesis Patients Pattern Perinatal Phenotype Play Proteins Recombinants Regulation Rett Syndrome Role Sampling Seizures Skeletal system Social Behavior Stereotyped Behavior Syndrome Testing Therapeutic Tissues Transcript Transforming Growth Factor beta Transgenic Model Viral Work age related behavior test disease phenotype improved in vivo insight loss of function mutation morphogens mouse Cre recombinase mouse methyl CpG binding protein 2 mouse model nerve stem cell nervous system disorder neurodevelopment neurogenesis neuropathology novel therapeutics pre-clinical prevent relating to nervous system targeted treatment transcriptome transcriptome sequencing virus genetics

项目摘要

PROJECT SUMMARY Loss-of-function mutations or duplication in methyl-CpG binding protein 2 (MECP2) cause two severe neurodevelopmental disorders: Rett syndrome and MECP2 duplication syndrome, respectively. While the genetic cause of these disorders is known, the mechanism by which disruption in MECP2 leads to pathogenesis is unknown; this has prevented the development of targeted therapies. Treatment with secreted factors has shown some efficacy in preclinical mouse models of MECP2-disorders. To identify candidate secreted factors misregulated by MeCP2, transcriptome profiles collected from Mecp2-null mouse models were evaluated, and Growth differentiation factor 11 (GDF11) was identified as a growth factor sensitive to MECP2-levels. GDF11 is downregulated in Mecp2-null models, while upregulated in MECP2-transgenic models. The opposing regulation of GDF11 by MECP2 implicates GDF11 misregulation as one potential shared mechanism between Rett and MECP2 duplication syndromes. GDF11 is a transforming growth factor beta family ligand that is a critical patterning morphogen for the skeletal system. However, despite broad expression throughout the brain, the role of GDF11 in brain development is unknown. The work proposed in this fellowship will test the hypothesis that GDF11 is a key morphogen for brain development, and that its misregulation in models of MECP2-disorders contributes to MECP2-disorder phenotypes. This hypothesis will be tested through the following specific aims: 1. Test if modulating brain specific dose of GDF11 by viral or genetic methods itself causes aberrant neurological phenotypes. 2. Test if normalization of GDF11 levels rescues neurological phenotypes seen in mouse models of MECP2- disorders. 3. Test the regulatory relationship between MECP2 and GDF11 by modeling the temporal changes in the transcriptome after perturbation of MECP2-levels to identify primary gene expression changes. The results from this fellowship will address three key questions in the field: 1) is GDF11 dose important in brain development, 2) does rescue of GDF11-levels ameliorate phenotypes in mouse models of MECP2-disorders, and 3) what are the primary gene expression changes that occur upon modulation of MECP2 levels.

项目概要甲基 CpG 结合蛋白 2 (MECP2) 的功能丧失突变或重复会导致两种严重的神经发育障碍：分别为 Rett 综合征和 MECP2 重复综合征。虽然这些疾病的遗传原因是已知的，MECP2 破坏导致发病机制的机制未知；这阻碍了靶向治疗的发展。用分泌因子治疗在 MECP2 疾病的临床前小鼠模型中显示出一定的功效。识别候选分泌因子 MeCP2 的错误调节，对从 Mecp2 缺失小鼠模型收集的转录组图谱进行了评估，并且生长分化因子 11 (GDF11) 被确定为对 MECP2 水平敏感的生长因子。 GDF11 是在 Mecp2 缺失模型中下调，而在 MECP2 转基因模型中上调。反对的规定 MECP2 对 GDF11 的影响表明 GDF11 的失调是 Rett 和 MECP2 重复综合征。 GDF11 是一种关键的转化生长因子β家族配体骨骼系统的图案形成素。然而，尽管在整个大脑中广泛表达，但该作用 GDF11 在大脑发育中的作用尚不清楚。该奖学金提出的工作将检验 GDF11 是大脑关键形态发生素的假设的发展，并且它在 MECP2 疾病模型中的错误调节导致了 MECP2 疾病表型。该假设将通过以下具体目标进行检验： 1.测试通过病毒或遗传方法调节大脑特定剂量的GDF11本身是否会导致异常神经表型。 2. 测试 GDF11 水平正常化是否可以挽救 MECP2- 小鼠模型中观察到的神经表型失调。 3. 通过对 MECP2 和 GDF11 的时间变化进行建模来测试 MECP2 和 GDF11 之间的调节关系。扰动 MECP2 水平后的转录组以确定主要基因表达变化。该研究金的结果将解决该领域的三个关键问题：1) GDF11 剂量对大脑是否重要 2) 拯救 GDF11 水平是否可以改善 MECP2 疾病小鼠模型的表型， 3) MECP2 水平调节时发生的主要基因表达变化是什么。