Genotypic and neuropathologic dissection of acquired periperal neuropathy in a canine model

犬模型获得性周围神经病的基因型和神经病理学解剖

基本信息

批准号：
9107928
负责人：
Susannah Sample
金额：
$ 14.43万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107928
关键词：
12 year old Advanced Development Affect Aging American Animal Model Animals Biopsy Breeding Canis familiaris Charcot-Marie-Tooth Disease Chromosome Mapping Chronic Clinical Clinical Treatment Clinical Trials Data Deglutition Demyelinations Denervation Deterioration Development Diabetes Mellitus Diagnosis Diagnostic tests Disease Disease Progression Dissection Foot Deformities Gene Mutation Genes Genetic Genetic Markers Genomics Genotype Goals Health Hereditary Disease Hereditary Motor and Sensory-Neuropathy Type II Histology Human Individual Inherited Investigation Knowledge Labrador Laryngeal Paralysis Larynx Lead Length Limb structure Link Linkage Disequilibrium Maps Modeling Motor Muscle Weakness Muscular Atrophy Mutation Nerve Nervous system structure Neural Conduction Neuropathy Outcome PMP22 gene Pathogenesis Pathologic Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Diseases Phenotype Physiological Physiology Polymorphism Analysis Population Predisposing Factor Predisposition Proteins Recurrent Laryngeal Nerve Research Schwann Cells Single Nucleotide Polymorphism Speech Symptoms Syndrome Targeted Resequencing Testing Tissues Variant Work afferent nerve age related autosomal dominant trait axonal degeneration base cell type chemotherapy chronic pain disorder subtype drug candidate genetic risk factor genetic variant genome wide association study innovation insight interest myelination nervous system disorder novel novel therapeutics screening spinal reflex trait treatment trial whole genome

项目摘要

DESCRIPTION (provided by applicant): Peripheral neuropathies are an important health problem for the American population. While peripheral neuropathies are commonly caused by diabetes and chemotherapy agents, a genetic-neuropathy, Charcot- Marie-Tooth disease (CMT), is the most common inherited neurologic disorder in people. CMT disease affects about 1 in 2,500 people in the USA. Symptoms of CMT are variable, but generally include chronic muscle weakness, foot deformities and limb muscle atrophy. Currently, there is no disease-modifying treatment for any CMT subtype. CMT is associated with mutations in genes that encode proteins involved in a variety of functions linked with myelination and axonal physiology. These mutations ultimately lead to impaired motor and sensory nerve function. Over 50 genes have been associated with CMT, although 4 genes (PMP22, MPZ, GJB1, and MFN2) are responsible for the majority of genetically diagnosed CMT. There are a substantial number of CMT patients where the genetic cause has not been identified. The most common forms of CMT are inherited in an autosomal dominant fashion. Dogs are also affected by a variety of peripheral neuropathies, which are generally breed-related, indicating a substantial genetic component. Our long-term goal is to develop an effective disease-modifying treatment for human CMT that could be used to block disease progression through testing drug candidates in a naturally occurring canine model. Therefore, the objective of this application is to determine the neuropathological features of canine acquired peripheral neuropathy (APN) and discover the genetic basis for the disease. The most prominent clinical feature of canine APN is laryngeal paralysis. APN is particularly common in the Labrador retriever. Many of the pathologic features of Labrador APN are similar to human peripheral neuropathy. The central hypothesis of this application is that canine APN will model an inherited human peripheral neuropathy. To accomplish the objective of this application we will pursue the following specific aims: 1) Determine neuropathological features of demyelination and axonal loss in dogs with a CMT- like APN and 2) Identify causal genetic variants that explain the CMT-like APN in the Labrador retriever. Under these aims, we will perform electro diagnostic testing, tissue biopsies, and whole genome single nucleotide polymorphism analysis of APN-affected cases and phenotype-negative controls. Causative variants will be identified through targeted re-sequencing of positional candidate regions of interest. The approach is innovative because it takes advantage of the high linkage disequilibrium within dog breeds to facilitate genetic mapping. Comprehensive understanding of the neuropathologic features and gene mutations associated with the APN trait is expected to enable development of a canine model for human peripheral neuropathy. Even if the causative mutation(s) are not associated with CMT-linked genes, this research may lead to the discovery of novel mutations associated with human peripheral nervous system disease.

描述（适用提供）：周围神经病是美国人群的重要健康问题。虽然周围神经病通常是由糖尿病和化学疗法引起的，但遗传性神经病，charcot-玛丽 - 牙齿疾病（CMT）是人中最常见的遗传性神经系统疾病。在美国，CMT疾病影响约1500人。 CMT的症状是可变的，但通常包括慢性肌肉无力，脚畸形和肢体肌肉萎缩。目前，对于任何CMT亚型都没有疾病改良的治疗方法。 CMT与编码与髓鞘化和轴突生理相关的各种功能的蛋白质的基因突变有关。这些突变最终导致运动和感觉神经功能受损。超过50个基因与CMT相关，尽管4个基因（PMP22，MPZ，GJB1和MFN2）负责大多数遗传诊断的CMT。尚未确定遗传原因的CMT患者数量很多。 CMT的最常见形式是以常染色体主导方式遗传的。狗还受到各种外周神经病的影响，这些神经病通常与繁殖有关，表明遗传成分很大。我们的长期目标是开发针对人CMT进行有效的疾病改良治疗方法，该治疗可用于通过在天然发生的犬类模型中测试候选药物来阻止疾病进展。因此，该应用的目的是确定犬科产生的周围神经病（APN）的神经病理特征，并发现该疾病的遗传基础。犬APN最突出的临床特征是喉麻痹。 APN在拉布拉多猎犬中尤为常见。 Labrador APN的许多病理特征类似于人类周围神经病。该应用的中心假设是犬APN将建模遗传的人周围神经病。为了实现本应用的目标，我们将追求以下特定目的：1）确定具有CMT样APN的狗的脱髓鞘和轴突丧失的神经病理学特征，并且2）确定解释Labrador回收室中类似CMT的APN的因果遗传变异。在这些目标下，我们将对受APN影响的病例和表型阴性对照组进行电诊断测试，组织活检和整个基因组单一核肽多态性分析。将通过针对性的候选候选区域进行针对性的重新确定感兴趣的区域来确定因果变体。这种方法具有创新性，因为它利用了狗品种内的高连接二极管来促进遗传图。对与APN性状相关的神经病理学特征和基因突变的全面理解有望为人类周围神经病的犬模型开发。即使严重的突变与CMT连接基因无关，这项研究也可能导致发现与人周围神经系统疾病相关的新型突变。