Understanding the cellular basis of Movement Disorders

了解运动障碍的细胞基础

基本信息

批准号：
8631893
负责人：
Puneet Opal
金额：
$ 37.88万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631893
关键词：
Abnormal coordination Address Adult Adverse effects Affect Alzheimer&apos s Disease Angiogenic Factor Ataxia Behavioral Behavioral Assay Biology Birth Brain Brain Stem CAG repeat Categories Cells Cerebellar Ataxia Cerebellum Clinical Trials Design Cytoplasmic Granules Disease Endothelial Cells Event Functional disorder Gene Expression Genes Genetic Glutamine Goals Health Hippocampus (Brain)Human Inferior Inherited Intraventricular Knock-in Mouse Knockout Mice Light Magnetic Resonance Imaging Mediating Modeling Motor Movement Disorders Mus Nature Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Olives - dietary Onset of illness Outcome Study Parkinson Disease Pathogenesis Pathology Patients Peptides Phenotype Play Property Proteins Purkinje Cells Recombinant Vascular Endothelial Growth Factor Recovery Role Route Schedule Signal Transduction Source Symptoms Syndrome Techniques Testing Therapeutic Therapeutic Agents Toxic effect Trinucleotide Repeat Expansion Type 1 Spinocerebellar Ataxia Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Work ataxin-1 autocrine base cytokine gene repression human VEGF protein improved insight mimetics mouse model mutant mutant mouse model nanoparticle nervous system disorder neurotrophic factor novel paracrine polyglutamine polyglutamine neurodegenerative diseases preclinical study prevent public health relevance research study

项目摘要

Spinocerebellar ataxia type 1 (SCA1) is one of nine late-onset neurodegenerative diseases caused by the expansion of a polyglutamine (CAG) repeat. In the case of SCA1, the pathogenic glutamine expansion affects ataxin-1 (ATXN1), a protein that plays a role in transcriptional repression. We and others have found that in SCA1 genetic mouse models, mutant ATXN1 alters gene expression as early as two weeks after birth, long before behavioral signs and other pathological events become evident. Given the early nature of these transcriptional aberrations, we predicted that altered expression of a few key genes plays a mediatory role in pathogenesis. In the course of testing this prediction, we made the unexpected discovery that ATXN1 directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF and that its levels are abnormally low in the SCA1 mouse brain. Following up on this observation, we discovered that genetically increasing VEGF levels mitigates the SCA1 phenotype in the well-characterized SCA1 knock-in mouse (SCA1154Q/2Q; Q=glutamine), the best existing mouse model of SCA1. We have also demonstrated in preliminary proof-of-principle experiments that VEGF delivered pharmacologically (by intraventricular delivery of recombinant VEGF) improves the cerebellar aspects of the SCA1 phenotype, specifically the hallmark ataxia and the cerebellar dendritic pathology. Motivated by these promising results, we wish to test two related hypotheses: that VEGF is an important cytokine for maintaining neurovascular health in the context of SCA1, and that VEGF has the potential to serve as therapy for this otherwise untreatable disease. We hope that these studies will provide mechanistic insights into the pathogenesis of SCA1 and also help design clinical trials for this disease. An important ancillary outcome of these studies is that they would shed light on the basic biology of VEGF in the nervous system and provide clues to its role in other neurodegenerative syndromes.

脊髓小脑共济失调 1 型 (SCA1) 是九种迟发性神经退行性疾病之一，由聚谷氨酰胺 (CAG) 重复序列的扩展。就 SCA1 而言，致病性谷氨酰胺扩张会影响 ataxin-1 (ATXN1)，一种在转录抑制中发挥作用的蛋白质。我们和其他人发现在 SCA1 遗传小鼠模型中，突变体 ATXN1 早在出生后两周就改变了基因表达，早在行为体征和其他病理事件变得明显。鉴于这些转录的早期性质畸变，我们预测一些关键基因的表达改变在发病机制中发挥中介作用。在在检验这个预测的过程中，我们意外地发现ATXN1直接调节血管生成和神经营养细胞因子 VEGF 的表达及其水平在 SCA1 中异常低老鼠的大脑。根据这一观察结果，我们发现基因上增加 VEGF 水平可以减轻已明确表征的 SCA1 敲入小鼠 (SCA1154Q/2Q；Q=谷氨酰胺) 中的 SCA1 表型，最好现有的SCA1小鼠模型。我们还在初步原理验证实验中证明了药物递送的 VEGF（通过脑室内递送重组 VEGF）可改善小脑 SCA1 表型的各个方面，特别是标志性共济失调和小脑树突病理学。有动力通过这些有希望的结果，我们希望检验两个相关的假设：VEGF 是一种重要的细胞因子。在 SCA1 的背景下维持神经血管健康，并且 VEGF 有潜力作为治疗这种原本无法治愈的疾病。我们希望这些研究能够提供有关机制的见解 SCA1 的发病机制，也有助于设计该疾病的临床试验。一个重要的辅助成果这些研究将阐明神经系统中 VEGF 的基本生物学并提供线索其在其他神经退行性综合征中的作用。