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Matrix Metalloproteinases: Therapeutic Targets For Huntington's Disease

基质金属蛋白酶：亨廷顿病的治疗靶点

基本信息

批准号：
8927075
负责人：
Lisa M Ellerby
金额：
$ 42.44万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
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：
2013-09-23 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927075
关键词：
Affect Apoptosis Behavioral Brain Brain-Derived Neurotrophic Factor Calpain Cardiovascular Diseases Caspase Cell Death Cells Chemistry Cleaved cell Corpus striatum structure Coupled DARPP Disease Disease Progression Disease model Dopamine D2 Receptor Drosophila genus Emotional Disturbance Enzyme Inhibition Enzymes Extracellular Matrix Proteins Family Family member Foundations Generations Genes Genetic Homologous Gene Human Human Genome Huntington Disease In Vitro Inherited Inhibition of Matrix Metalloproteinases Pathway Kidney Diseases Knock-out Knockout Mice Length Malignant Neoplasms Mass Spectrum Analysis Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Mediator of activation protein Methods Molecular Movement Mus N-terminal Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Pattern Peptide Hydrolases Plant Resins Play Process Production Property Protease Gene Proteins Proteolysis Rheumatoid Arthritis Role Sampling Signal Pathway Synapses Testing Therapeutic Tissue Inhibitor of Metalloproteinases Tissues Toxic effect Universities Work Zinc base cannabinoid receptor drug development effective therapy enzyme activity genome-wide analysis human Huntingtin protein human MMP14 protein human disease in vivo inhibitor/antagonist interest knock-down loss of function member mouse model mutant novel novel diagnostics polyglutamine prevent public health relevance stromelysin 2 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease characterized by emotional disturbances, uncontrolled movements and loss of intellectual abilities. As the disease progresses a massive loss of striatal and cortical neurons results from the expression of the mutant huntingtin protein containing an expanded polyglutamine tract. An important pathologic feature of HD is the production of toxic expanded polyglutamine containing N-terminal fragments that result in aggregates found in the brain. Cleavage of Htt is known to occur through caspases and calpains. However, the role of proteases in HD has not been systematically investigated. In our preliminary studies we used a genome-wide screen of protease family members to identify modifiers of huntingtin proteolysis and toxicity. We found 11 proteases that reduce the production of huntingtin fragments. Three of those proteases are members of the matrix metalloproteinase (MMP) family. We found one of these, MMP-10, cleaves huntingtin directly, and prevents cell death when knocked down in striatal HdhQ111/Q111 cells. Correspondingly, we found MMPs are activated in mouse models of HD, and loss-of- function of Drosophila homologs of MMPs suppress Ht-induced neuronal dysfunction in vivo. We have therefore identified an interesting and novel mechanism of proteolysis and toxicity for HD. In this application, we will further study the role of MMPs in the molecular pathways leading to striatal cell death. We will determine how MMPs affect the processing of Htt in brain samples of HD mouse models. Furthermore, we will investigate if pharmacological or genetic reduction of MMP-10 or MMP-14 modifies disease progression or pathogenesis in HD mouse models. By crossing MMP-10 or MMP-14 knockout mice to HD mouse models, we will determine if deficiency of MMPs in the brain can ameliorate HD-like pathologies or behavioral deficits in HD mice. We will also use MMP inhibitors to treat HD mouse models and determine if HD pathogenesis or disease progression is modified by treatment. Together, our studies will determine if MMP are valid targets for HD treatment.

描述(申请人提供)：亨廷顿病(HD)是一种致命性常染色体显性遗传性神经退行性疾病，以情绪障碍、失控运动和智力丧失为特征。随着疾病的发展，纹状体和皮质神经元的大量损失是由于突变的亨廷顿蛋白的表达导致的，该蛋白包含一个扩展的聚谷氨酰胺束。HD的一个重要病理特征是产生含有N-末端片段的有毒膨胀聚谷氨酰胺，导致在大脑中发现聚集体。已知Htt的切割是通过半胱氨酸酶和钙蛋白酶发生的。然而，蛋白水解酶在HD中的作用还没有得到系统的研究。在我们的初步研究中，我们使用了全基因组的蛋白酶家族成员筛选来鉴定亨廷顿蛋白分解和毒性的修饰物。我们发现了11种减少亨廷顿蛋白片段产生的蛋白酶。其中三种蛋白是基质金属蛋白酶家族的成员。我们发现其中的一种，基质金属蛋白酶-10，直接切割亨廷顿蛋白，并在纹状体HdhQ111/Q111细胞中被击倒时防止细胞死亡。相应地，我们发现MMPs在HD小鼠模型中被激活，并且MMPs的果蝇同源物的功能丧失在体内抑制了Ht诱导的神经元功能障碍。因此，我们确定了HD的一种有趣而新颖的蛋白分解和毒性机制。在这一应用中，我们将进一步研究MMPs在导致纹状体细胞死亡的分子途径。我们将在HD小鼠模型的大脑样本中确定MMPs如何影响Htt的处理。此外，我们将研究是否药物或遗传减少的基质金属蛋白酶-10或基质金属蛋白酶-14改变疾病的进展或在HD小鼠模型的发病机制。通过将MMP10或MMP14基因敲除的小鼠与HD小鼠模型杂交，我们将确定大脑中MMPs缺乏是否可以改善HD小鼠的类似HD的病理或行为缺陷。我们还将使用基质金属蛋白酶抑制剂治疗HD小鼠模型，并确定HD的发病机制或疾病进展是否通过治疗而改变。总之，我们的研究将确定基质金属蛋白酶是否是HD治疗的有效靶点。