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Examining Progression of a Neurodegenerative Disorder

检查神经退行性疾病的进展

基本信息

批准号：
10056517
负责人：
Mohammad Moshahid Khan
金额：
$ 15.2万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056517
关键词：
3 year old Address Advanced Development Affect Age Age-Months Alleles Animal Disease Models Apoptosis Architecture Autophagocytosis Behavioral Binding Brain Brain region Cell Nucleolus Cell Survival Cell physiology Cells Cerebellum Cerebral cortex Characteristics Childhood Cognitive Comprehension DNA Damage DNA-Directed RNA Polymerase Development Disease Disease Progression Event Expression Profiling Fibroblasts Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genotype Glutamic Acid Goals Histopathology Human Impaired cognition Individual Intervention Knowledge Lead Lysine Mission Molecular Monitor Morbidity - disease rate Motor Mus Mutant Strains Mice Mutate Mutation Names Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Disorder Neurologic Neurologic Symptoms Neurons Nucleolar Proteins Pathologic Pathway interactions Patients Phenotype Play Population Process Public Health Quality of life RNA chemical synthesis Recurrence Research Ribosomal RNA Role Sensorimotor functions Syndrome System Testing Therapeutic Therapeutic Intervention Time Transcription Regulatory Protein Tremor United States National Institutes of Health Variant Weight Wild Type Mouse base brain cell cerebral atrophy cognitive ability cognitive function disability experimental study innovation insight mouse model nervous system disorder novel therapeutic target transcription factor transcriptome sequencing

项目摘要

There is a fundamental gap in understanding how the underlying mutation leads to a recently identified disease called UBTF E210K Neuroregression Syndrome (UNS), a debilitating neurodevelopmental disorder. UNS is associated with a variant of UBTF, a transcriptional regulatory protein, in which glutamic acid at reside 210 is mutated to a lysine (E210K). The onset of UNS is about 2.5 to 3 years of age. In order to study UNS, we have generated a UBTF+/E210K mouse as a novel animal model of this disease. Increased comprehension of disease progression will identify the pathways and molecules that could serve the role of potential therapeutic targets. The long-term goal is to develop therapeutic intervention that decrease morbidity of this devastating illness. The objective in this application is to examine the histopathology of the brain in UBTF+/E210K and UBTFE210K/E210K mice at different ages, and the gene expression profiles in the cerebellum and cortex of WT and UBTF+/E210K mice. The central hypothesis is that increased levels of DNA damage and apoptosis will correlate with sensorimotor, behavioral and neurological phenotypes. The experiments in this proposal will be guided by two Specific Aims: 1) Examine and compare the histopathology and gene expression profile of brains from UBTF+/+ (wild-type), UBTF+/E210K, and UBTFE210K/E210K mice during disease progression. and 2) Identify the brain regions and cell populations implicated in sensorimotor and cognitive dysfunction. In the first aim, cellular characteristics such as DNA damage, apoptosis and gene expression profile will be monitored in brains from wild-type and mutant mice at different ages. In the second aim, we will identify the brain regions and vulnerable cell populations and corelate with behavioral abnormalities. The approach is innovative because disease progression of UNS is poorly understood and we take advantage of a novel mouse model to overcome the issues with performing these experiments in a human system. The proposed research is significant because it is expected to substantially advance our understanding of disease progression and identify potential pathways and molecules that are the most likely targets of disease modifying intervention for the debilitating UTBF E210K Neuroregression Syndrome.

在理解潜在突变如何导致最近发现的疾病方面存在根本差距称为 UBTF E210K 神经退行综合症 (UNS)，一种使人衰弱的神经发育障碍。联合国系统是与 UBTF 的变体相关，UBTF 是一种转录调节蛋白，其中 210 位的谷氨酸是突变为赖氨酸 (E210K)。 UNS 的发病年龄约为 2.5 至 3 岁。为了学习UNS，我们已经建立了 UBTF+/E210K 小鼠作为这种疾病的新型动物模型。加深对以下内容的理解疾病进展将确定可以发挥潜在治疗作用的途径和分子目标。长期目标是开发治疗干预措施，降低这种破坏性的发病率疾病。本应用的目的是检查 UBTF+/E210K 中大脑的组织病理学和 UBTFE210K/E210K不同年龄小鼠及WT小脑和皮质基因表达谱和 UBTF+/E210K 小鼠。中心假设是 DNA 损伤和细胞凋亡水平的增加会与感觉运动、行为和神经表型相关。本提案中的实验将是以两个具体目标为指导：1）检查并比较组织病理学和基因表达谱疾病进展期间 UBTF+/+（野生型）、UBTF+/E210K 和 UBTFE210K/E210K 小鼠的大脑。和 2) 识别与感觉运动和认知功能障碍有关的大脑区域和细胞群。在第一个目标中，DNA 损伤、细胞凋亡和基因表达谱等细胞特征将被对不同年龄的野生型和突变型小鼠的大脑进行监测。在第二个目标中，我们将确定大脑区域和脆弱的细胞群，并与行为异常相关。方法是创新，因为 UNS 的疾病进展知之甚少，并且我们利用了一种新型小鼠模型来克服在人体系统中进行这些实验的问题。拟议的研究意义重大，因为它有望大大提高我们对疾病进展的理解，确定潜在的途径和分子，它们是疾病改变干预措施最有可能的目标令人衰弱的 UTBF E210K 神经退行综合症。