Investigating the Role of MS4As in Amyotrophic Lateral Sclerosis

研究 MS4As 在肌萎缩侧索硬化症中的作用

基本信息

批准号：
10751695
负责人：
Abigail Jean Hiller
金额：
$ 3.5万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751695
关键词：
ALS patients Address Adult Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyotrophic Lateral Sclerosis Animal Model Animals Attenuated Behavioral Biological Assay Brain Brain Stem Cell Death Cells Central Nervous System Cessation of life Chemoreceptors Coronary Arteriosclerosis Corticospinal Tracts Data Defect Development Diagnosis Disease Disease associated microglia Disease model Elderly Exhibits Family Family member Functional disorder Future Gene Cluster Gene Expression Profile Gene Family Genes Genetic Polymorphism Genetic Transcription Gliosis Histologic Huntington Disease Immune system Incidence Individual Inflammatory Knock-out Knockout Mice Knowledge Link Longevity Macrophage Malignant Neoplasms Mediating Mediator Membrane Microglia Motor Motor Neuron Disease Motor Neurons Multiple Sclerosis Mus Muscle Weakness Neurodegenerative Disorders Neuroimmune Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Phagocytosis Phenotype Play Population Process Prognosis Property Reagent Research Risk Role Series Single Nucleotide Polymorphism Spinal Cord Synapses System Testing United States Up-Regulation Work age related neurodegeneration aging population cognitive function disease phenotype effective therapy experimental study frontal lobe functional restoration genome wide association study human model human old age (65+)improved in vivo insight interest member motor deficit motor function improvement motor neuron degeneration mouse genetics mouse model neuroinflammation neuron loss novel novel therapeutics physically handicapped protective allele protein expression receptor response sex single-cell RNA sequencing targeted treatment therapeutic development therapy development transcriptomics

项目摘要

Project Abstract (30 lines) Neurodegenerative diseases (NDDs) are devastating conditions that rob individuals of their cognitive function, mobility, and ability to function in the world. Ultimately, many of these diseases are fatal. Today, a combined 6.5 million Americans suffer from NDDs, encompassing Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). However, by 2030, 1 in 5 Americans will be over the age of 65, and because NDDs strike primarily in mid- to late-life, the incidence is expected to soar as our population ages. These circumstances highlight the increasing urgency for the development of effective treatments and cures for NDDs, which are currently lacking. While NDDs differ in their inciting mechanisms, research has now clearly demonstrated the presence of shared features of downstream pathophysiology, notably, the role of a dysregulated neuroinflammatory system. Recent studies in humans and animal models have uncovered a population of microglia (Disease-associated microglia, DAMs), that are defined by a distinct transcriptional signature, and are conserved across several different NDDs. Intriguingly, the DAM signature includes upregulation of a number of different members of the MS4A gene family, for which polymorphisms have been linked to AD by numerous genome-wide association studies (GWAS). The upregulation of AD-associated MS4A genes in DAMs begs the questions of whether MS4A genes might play a common role in NDDs, which share a DAM signature, and furthermore, whether MS4A genes impact the functional properties of microglia in the context of NDDs. Excitingly, our lab has found that across three animal NDD models (5XFAD, MAPT, SOD1G93A), mice deficient for either of two individual Ms4a family members exhibit improved disease phenotypes, extension of lifespan, and amelioration of histopathological disease hallmarks. Thus, this proposal will test the hypothesis that multiple MS4As act in concert to drive pathology in a mouse model of ALS and regulate microglial transcriptional as well as functional responses to the NDD milieu. To test this hypothesis, aim 1 will investigate the impact of simultaneous deletion of the entire MS4A gene family on ALS. To this end, we have generated a novel mouse genetic reagent in which the entire MS4A gene cluster is deleted. These mice will be crossed to the SOD1G93A ALS mouse model and pathological features of ALS, including motor defects, lifespan, microgliosis, neuronal loss, and synapse elimination will be assessed. Aim 2 will examine the impact of MS4A deficiency on the transcriptional and functional properties of spinal cord microglia isolated from end-stage SOD1G93A mice. Specifically, I will utilize single-cell RNA sequencing (scRNA-seq) in tandem with spatial transcriptomics (MERFISH) to evaluate the impact of MS4A deletion on the DAM population. In parallel, I will examine how MS4A deficiency in vivo affects the key microglial function of phagocytosis. Together, these aims will provide fundamental new insight into the role of MS4As in ALS and contribute to the development of therapeutic approaches targeting MS4A receptors.

项目摘要（30行）神经退行性疾病（NDDS）是破坏性的疾病，使个人具有认知功能，流动性和在世界上运作的能力。最终，其中许多疾病是致命的。今天，一个合并 650万美国人患有NDD，包括阿尔茨海默氏病（AD），帕金森氏病（PD），多发性硬化症（MS），肌萎缩性侧面硬化症（ALS）和亨廷顿氏病（HD）。但是，通过 2030年，五分之一的美国人将超过65岁，并且由于NDDS在后期至后期的初级罢工，所以随着我们人口的年龄，预计发病率将飙升。这些情况强调了越来越多的紧迫性目前缺乏的NDD的有效治疗和治疗方法的开发。虽然NDD不同他们的煽动机制，研究现在清楚地证明了存在的共同特征下游病理生理学，尤其是神经炎症系统失调的作用。最近的研究人类和动物模型发现了小胶质细胞（与疾病相关的小胶质细胞，大坝）的种群，由不同的转录签名定义，并在几个不同的NDD上配置。有趣的是，大坝的签名包括MS4A基因的许多不同成员的上调众多基因组关联研究已将多态性与AD联系在一起的家族。（GWAS）。大坝中与AD相关的MS4A基因的上调引发了MS4A是否的问题基因可能在NDD中起共同的作用，该NDD共享大坝签名，此外，是否MS4A 基因在NDD的背景下影响小胶质细胞的功能特性。令人兴奋的是，我们的实验室发现在三种动物NDD模型（5xFAD，MAPT，SOD1G93A）中，两种单独的MS4A中的任何一个都缺乏小鼠家庭成员表现出改善的疾病表型，寿命的延长以及改善组织病理学疾病标志。这是该提议将检验以下假设：多个MS4A在在ALS的小鼠模型中驱动病理的音乐会，并调节小胶质转录和功能对NDD环境的回应。为了检验这一假设，AIM 1将研究简单删除的影响在ALS上的整个MS4A基因家族中。为此，我们在整个MS4A基因簇被删除。这些小鼠将越过SOD1G93A ALS鼠标模型 ALS的病理特征，包括运动缺陷，寿命，小胶质细胞增多，神经元丧失和突触消除将被评估。 AIM 2将检查MS4A缺乏对转录和从末期SOD1G93A小鼠分离的脊髓小胶质细胞的功能特性。具体来说，我将使用单细胞RNA测序（SCRNA-SEQ）与空间转录组学（Merfish）串联以评估同时，我将研究MS4A在体内的缺失如何影响吞噬作用的关键小胶质功能。这些目标将共同提供基本的新见解 MS4A在ALS中的作用，并有助于针对MS4A接收器的理论方法的发展。