Neurodevelopmental role of a tRNA methyltransferase underlying intellectual disability

tRNA 甲基转移酶对智力障碍的神经发育作用

基本信息

批准号：
10677608
负责人：
Kimberly Rose R. Madhwani
金额：
$ 4.87万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10677608
关键词：
Address Adverse effects Affect Alleles Amino Acids Animals Anticodon Antioxidants Attenuated Bioinformatics Biological Models CRISPR/Cas technology Code Codon Nucleotides Communication Data Degenerative Disorder Development Development Plans Disease Drosophila genus Drug Screening Educational process of instructing Educational workshop Electrophysiology (science)Enzymes Event Family Foundations Gene Expression Gene Expression Regulation Genes Genetic Global Change Growth Homologous Gene Human Image Individual Intellectual functioning disability Laboratories Lead Ligase Link Mentors Mentorship Methylation Missense Mutation Modeling Modification Molecular Mutation Nerve Degeneration Nervous System Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Effect Neurological Models Neurons Neurosciences Oxidative Stress Pathway interactions Patients Phase Phenotype Pluripotent Stem Cells Positioning Attribute Postdoctoral Fellow Proteomics RNA Stability Reactive Oxygen Species Regulation Research Research Personnel Research Project Grants Role Science Selenocysteine Side Structure Synapses System Testing Therapeutic Training Transfer RNA Translations Uridine Variant Work Yeasts behavioral study candidate identification combat experience experimental study induced pluripotent stem cell insight interest mRNA Translation mutant nervous system development nervous system disorder neurodevelopment pharmacologic polypeptide post-doctoral training posttranscriptional pre-doctoral response restraint screening selenophosphate selenoprotein skills small molecule synaptogenesis tRNA Methyltransferases teacher transcriptomics treatment strategy

项目摘要

PROJECT SUMMARY Gene regulation at multiple levels is critical for nervous system development and function. A number of mutations leading to global dysregulation of gene expression have been found to disproportionately affect the nervous system, leading to neurodevelopmental and neurodegenerative disorders. Transfer RNAs (tRNAs), which recognize codons and add the appropriate amino acid to growing polypeptides, can dynamically regulate translation. tRNAs are heavily post-transcriptionally modified to regulate their structure, stability, and fidelity. ALKBH8 is one of two metazoan homologs of the yeast tRNA methyltransferase TRM9. Stop and missense mutations in human ALKBH8 have recently been shown to cause intellectual disability in four families. However, ALKBH8’s role in the nervous system remains unknown. To address this, I have generated null alleles in Drosophila and found that ALKBH8 regulates synapse formation. My preliminary data suggest ALKBH8 attenuates synaptic growth by limiting oxidative stress through the methylation of tRNA- selenocysteine, which yields the rare 21st amino acid selenocysteine for the synthesis of selenoproteins. In AIM 1, I will employ genetic, pharmacological, imaging, and bioinformatic approaches in Drosophila to define the links between ALKBH8, selenoproteins, and synaptic growth and investigate the impact of a human ALKBH8 mutation in the nervous system. In AIM 2, I will build on the skills gained during my dissertation work by expanding into human-derived pluripotent stem cells (iPSCs) to model neurological disorders and probe potential treatment strategies. The proposed experimental plan will provide mechanistic insight into how tRNA modifications regulate gene expression during nervous system development. The proposed training plan will provide me with the technical, academic, and professional skillset to thrive for the remainder of my predoctoral training and beyond as I transition into a postdoctoral position. Successful completion of the F99/K00 aims will place me in a unique position to investigate mechanisms underlying neurodevelopment disorders in two model systems with complementary strengths and identify potential therapeutic treatments for affected individuals.

项目摘要多个级别的基因调节对于神经系统的发展和功能至关重要。许多发现导致基因表达全球失调的突变已过度影响转移RNA（TRNA），导致神经发育和神经退行性疾病。识别密码子并将适当的氨基酸添加到生长的多肽中，可以动态调节翻译。 TRNA经过大量的转录后修改，以调节其结构，稳定性和忠诚度。 ALKBH8是酵母TRNA甲基转移酶TRM9的两个后生同源物之一。停下来和错过最近已显示人类ALKBH8中的突变会导致四个家庭的智力残疾。但是，ALKBH8在神经系统中的作用仍然未知。为了解决这个问题，我已经生成了空果蝇中的等位基因发现ALKBH8调节突触形成。我的初步数据暗示 ALKBH8通过通过tRNA的甲基化限制氧化物应激来减轻突触的生长硒代半胱氨酸产生稀有的21氨基酸硒代半胱氨酸，用于合成硒蛋白。目标 1，我将在果蝇中采用遗传，药物，成像和生物信息学方法来定义 ALKBH8，硒蛋白和突触生长之间的联系并研究人类ALKBH8的影响神经系统中的突变。在AIM 2中，我将基于在论文工作期间获得的技能扩展为人类衍生的多能干细胞（IPSC），以建模神经系统疾病并证明潜在的治疗策略。提出的实验计划将提供有关tRNA修饰如何调节基因的机械洞察力神经系统发育期间的表达。拟议的培训计划将为我提供技术，学术和专业技能，在我的剩余培训及以后的剩余时间里蓬勃发展过渡到博士后位置。成功完成F99/K00 AIMS将使我处于独特之处在两个模型系统中研究神经发育障碍的基础机制的位置完全优势并确定受影响个体的潜在治疗治疗。