Analysis of a mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

具有轴突球体和色素神经胶质的成人发病白质脑病小鼠模型的分析。

基本信息

批准号：
9473903
负责人：
E. RICHARD STANLEY
金额：
$ 2.37万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9473903
关键词：
Address Adult Age Age-Months Aging Alleles Alzheimer&apos s Disease Anatomy Appearance Behavior Behavioral Brain CSF1R gene CSF3 gene Cell Count Cell Survival Cells Cessation of life Characteristics Cognitive Colony Stimulating Factor Activation Data Dementia Development Diagnosis Diffuse Disease Early Diagnosis Epilepsy Etiology Exhibits Genes Genetic Granulocyte-Macrophage Colony-Stimulating Factor Histologic Hormones Human Characteristics Infection Inflammatory Inherited Injury Institutes Leukoencephalopathy Ligands MRI Scans Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Magnetic Resonance Imaging Maintenance Mediating Mental Depression Methods Microglia Modeling Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Differentiation Neurons Pathogenesis Patients Phenotype Phosphotransferases Pigments Play Proteins Radiology Specialty Receptor Signaling Recovery Regulation Residual state Role Signal Transduction Testing Therapeutic Woman X-Ray Computed Tomography anxiety-like behavior base brain cell cytokine density effective therapy genetic approach granulocyte histopathological examination human disease inflammatory marker leukodystrophy loss of function men motor impairment mouse model nerve stem cell neuron development neuron loss neuronal survival novel public health relevance receptor receptor expression receptor-mediated signaling repaired

项目摘要

DESCRIPTION (provided by applicant): Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), is a rare, autosomal dominant, neurodegenerative disorder that is characterized by adult-onset dementia with motor impairments and epilepsy. ALSP encompasses two similar diseases previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD). The disease is caused by dominant mutations in the colony stimulating factor-1 receptor gene (CSF1R) resulting in loss of function, or of expression, of one allele. We have identified the heterozygous Csf1r+/- mouse as a model of ALSP. Csf1r+/- mice exhibit cognitive and sensorimotor deficits and depression- and anxiety- like behavior characteristic of early ALSP. MRI of Csf1r+/- brains reveals similarities to the radiologic changes in ALSP. Histopathological examination indicates neuronal loss, neuronal degeneration with presence of axonal spheroids and microgliosis, that are characteristic of the human disease. It is not known whether developmental deficits contribute to ALSP, nor whether loss of a single copy of the Csf1r gene in neurons and/or microglia is most critical for disease pathogenesis. Furthermore, there are no effective treatment options for ALSP. Our mouse model of ALSP will enable these questions to be addressed, early detection methods identified and novel treatment approaches instituted. The Overall Aim is to utilize our mouse model of ALSP to determine the contributions of development, aging, microglial and neuronal lineages to disease pathogenesis and to explore therapeutic strategies based on these findings. In Specific Aim 1, we will determine the nature and cellular origins of developmental abnormalities in Csf1r haploinsufficient mice. The nature and timing of the appearance of histopathologic changes in the developing brains of Csf1r+/- mice, will be examined, the role of Csf1r haploinsufficiency in the microglial and/or neuronal lineages assessed and regulation by inappropriately elevated cytokines elucidated. In Specific Aim 2, we will determine the necessity of microglial and/or neuronal regulation by the CSF-1R for disease development by genetic deletion of a single Csf1r allele in the microglial and/or neuronal lineages of mice. In Specific Aim 3, we will identify targets for the treatment of ALSP. The proposed studies are relevant not only for our understanding of ALSP, but also with respect to other neurodegenerative disorders in which neuronal cell survival and microglial function are critical. They will also directly contribute to our understanding of the roles of CSF-1R signaling n neuronal development and the regulation of microglia.

描述（由应用提供）：带有轴突球形的成人白细胞术和木质神经胶质（ALSP），是一种罕见的，常染色体显性的，神经退行性疾病，具有运动障碍和癫痫病的成人痴呆症的特征。 ALSP包含两种以前称为遗传性弥漫性白血病患病的类似疾病，伴有轴突球形（HDLS）和家族色素正化性白细胞营养不良（POLD）。该疾病是由刺激因子1受体基因（CSF1R）中的显性突变引起的，导致一个等位基因的功能或表达丧失。我们已经将杂合CSF1R +/-小鼠确定为ALSP的模型。 CSF1R +/-小鼠暴露了早期ALSP的认知和感觉运动缺陷以及抑郁症和类似动画的行为特征。 CSF1R +/-大脑的MRI显示与ALSP的放射学变化相似。组织病理学检查表明神经元丧失，神经元变性，存在轴突球形的存在和小胶质细胞增多，这是人类疾病的特征。尚不清楚发育缺陷是否有助于ALSP，也不知道神经元和/或小胶质细胞中CSF1R基因的单个副本的丧失是否对疾病发病机理最为重要。此外，ALSP没有有效的治疗选择。我们的ALSP小鼠模型将使这些问题得以解决，确定的早期检测方法以及提出的新型治疗方法。总体目的是利用我们的ALSP小鼠模型来确定发展，衰老，小胶质细胞和神经元谱系对疾病发病机理的贡献，并基于这些发现探索热策略。在特定的目标1中，我们将确定CSF1R单倍弹性小鼠发育异常的性质和细胞起源。将研究CSF1R +/-小鼠发展中组织病理学变化的出现的性质和时机，CSF1R单倍型在小胶质细胞和/或神经元谱系中通过不当升高的细胞因子阐明了CSF1R单倍型的作用。在特定的目标2中，我们将通过CSF-1R来确定小鼠小鼠和/或神经元谱系中单个CSF1R等位基因的遗传缺失对CSF-1R进行疾病发育的必要性。在特定目标3中，我们将确定治疗ALSP的靶标。提出的研究不仅与我们对ALSP的理解有关，而且与其他神经退行性疾病有关，其中神经元细胞存活和小胶质细胞功能至关重要。他们还将直接有助于我们理解CSF-1R信号传导N神经元发育和小胶质细胞的调节的作用。