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。

• 批准号: 9028652
• 负责人: E. RICHARD STANLEY
• 金额: $ 51.79万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028652
• 关键词: Address; Adult; Age; Age-Months; Aging; Alleles; Alzheimer' s Disease; Appearance; Behavior; Brain; CSF1R gene; Cell Count; Cell Survival; Cells; Cessation of life; Characteristics; Cognitive; Data; Dementia; Development; Diffuse; Disease; Early Diagnosis; Epilepsy; Etiology; Exhibits; Genes; Genetic; Granulocyte-Macrophage Colony-Stimulating Factor; Hormones; 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; Population; Proteins; Receptor Signaling; Recovery; Regulation; Residual state; Role; Signal Transduction; Staging; Testing; Therapeutic; Time; Woman; X-Ray Computed Tomography; anxiety-like behavior; base; brain cell; cytokine; density; effective therapy; genetic approach; granulocyte; 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 expression; receptor-mediated signaling; repaired

 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(申请人提供)：成人起病的白质脑病轴突球体和神经胶质色素沉着(ALSP)，是一种罕见的常染色体显性遗传性神经退行性疾病，其特征是成人起病的痴呆伴运动障碍和癫痫。ALSP包括两种类似的疾病，以前被称为遗传性弥漫性白质脑病伴轴索球形(HDLS)和家族性色素正色脑白质营养不良(POLD)。这种疾病是由集落刺激因子-1受体基因(CSF1R)的显性突变引起的，导致一个等位基因的功能或表达丧失。我们已将杂合子CSF1R+/-小鼠确定为ALSP的模型。CSF1R+/-小鼠表现出认知和感觉运动障碍以及早期阿尔茨海默病的抑郁和焦虑样行为特征。CSF1R+/-脑的MRI表现与ALSP的放射学改变相似。组织病理学检查显示神经元丢失、神经元变性并存在轴突球体和小胶质细胞增多症，这是人类疾病的特征。目前尚不清楚发育缺陷是否与ALSP有关，也不清楚神经元和/或小胶质细胞中CSF1R基因的单拷贝丢失是否在疾病发病机制中起最关键的作用。此外，目前还没有有效的治疗ALSP的方法。我们的ALSP小鼠模型将能够解决这些问题，识别早期检测方法，并建立新的治疗方法。总体目标是利用我们的ALSP小鼠模型来确定发育、衰老、小胶质细胞和神经元谱系在疾病发病机制中的贡献，并基于这些发现探索治疗策略。在特定目标1中，我们将确定CSF1R单倍体缺陷小鼠发育异常的性质和细胞来源。将研究CSF1R+/-小鼠发育中大脑组织病理学变化的性质和出现的时间，评估CSF1R单倍体缺陷在小胶质细胞和/或神经元谱系中的作用，并阐明不适当升高的细胞因子的调节。在具体目标2中，我们将通过小鼠小胶质细胞和/或神经元谱系中单个CSF1R等位基因的遗传缺失来确定小胶质细胞和/或神经元在疾病发展中由CSF-1R调节的必要性。在具体目标3中，我们将确定治疗ALSP的目标。建议的研究不仅与我们对ALSP的理解有关，也与其他神经退行性疾病有关，在这些疾病中，神经细胞生存和小胶质功能至关重要。它们还将直接有助于我们理解CSF-1R信号在神经元发育和小胶质细胞调节中的作用。