权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Modulation of astrocyte-mediated neurotoxicity by NR1D1 in ALS models

ALS 模型中 NR1D1 调节星形胶质细胞介导的神经毒性

基本信息

批准号：
10800001
负责人：
Mariana Atina Pehar
金额：
$ 53.78万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10800001
关键词：
ALS patients Adult Agonist Amyotrophic Lateral Sclerosis Astrocytes Autopsy Brain Stem Cause of Death Cell Culture Techniques Cells Central Nervous System Circadian Rhythms Coculture Techniques Data Disease Disease Progression Down-Regulation Fibroblasts Functional disorder Genes Goals Homeostasis Human Inflammation Inflammatory Inflammatory Response Link Mammals Mediating Metabolic Metabolism Mitochondria Modeling Molecular Motor Cortex Motor Neuron Disease Motor Neurons Movement Mus Muscle Weakness NF-kappa B Nerve Degeneration Neuroglia Neurons Nuclear Receptors Paralysed Pathologic Pathway interactions Phenotype Play Process Proteins Proteomics Regulation Reporting Role Signal Transduction Skeletal Muscle Specificity Spinal Cord Symptoms Testing Therapeutic Tissues Toxic effect Transcription Repressor Transgenic Organisms adeno-associated viral vector cell type defined contribution familial amyotrophic lateral sclerosis flexibility fused in sarcoma gene therapy glucose metabolism in vivo induced pluripotent stem cell insight knock-down lipid metabolism member metabolomics mitochondrial dysfunction molecular clock motor neuron degeneration mouse model multiple omics mutant nerve stem cell neuroinflammation neuron loss neuronal survival neurotoxic neurotoxicity new therapeutic target novel novel therapeutic intervention overexpression pharmacologic pre-clinical small molecule superoxide dismutase 1 transcriptomics

项目摘要

Abstract ALS or Lou Gehrig's disease is the most common adult-onset motor neuron disease, characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Motor neuron death leads to muscle weakness and paralysis, usually causing death in one to five years after symptoms onset. The molecular mechanisms responsible for motor neuron degeneration in ALS remain uncertain. However, several lines of evidence indicate that dysfunction of glial cells significantly contributes to the neurodegenerative process. Astrocytes, key regulators of central nervous system homeostasis, have been shown to play a major role in the progression of the disease. Accordingly, in cell culture models, astrocytes isolated from ALS mouse models or astrocytes differentiated from fibroblast-derived induced pluripotent stem cells (iPSCs) from sporadic and familial ALS patients, induce motor neuron death. Astrocytes have a key role in the metabolic support of neurons, and lack of metabolic flexibility and mitochondrial dysfunction are hallmarks of ALS astrocytes. We recently showed that NR1D1 plays a critical role in the regulation of astrocyte-motor neuron interaction. NR1D1 is a member of the nuclear receptor superfamily and it is an essential component of the molecular clock in mammals. NR1D1 is also a known repressor of metabolic and inflammatory genes, and has been shown to regulate mitochondrial number and function, glucose and lipid metabolism, and inflammation during normal and pathological conditions. We recently reported that NR1D1 expression decreases in the spinal cord of symptomatic ALS mice. Moreover, we showed that the knockdown of Nr1d1 expression in primary mouse spinal cord astrocyte cultures, or in iPSC- derived human astrocytes, activates NF-kB signaling and induces a pro-inflammatory phenotype that is detrimental for the survival of co-cultured motor neurons. In addition, our preliminary data shows that iPSC- derived astrocytes from ALS patients display lower levels of NR1D1 expression when compared to astrocytes derived from healthy controls. In this proposal, we will investigate the role of NR1D1 in the regulation of astrocyte- motor neuron interaction and the therapeutic potential of targeting NR1D1 in ALS. We will perform an unbiased multi-omic analysis to outline the mechanism by which NR1D1 downregulation induces a neurotoxic phenotype in human iPSC-derived astrocytes (Aim 1). In addition, we will use different approaches to evaluate the effect of modulating NR1D1 expression on the progression of the disease in an ALS mouse model (Aims 2 and 3). The results obtained will contribute to the current understanding of the mechanisms involved in the toxicity of astrocytes towards motor neurons in ALS. In addition, this proposal will establish the therapeutic value of targeting NR1D1 to slow or halt the progression of the disease in an ALS mouse model.

摘要