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

• 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
• 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' s Disease; Alzheimer' 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

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（NDD）是剥夺个体认知功能的破坏性疾病， 流动性和在世界上发挥作用的能力。最终，这些疾病中有许多是致命的。今天， 6.5数百万美国人患有NDD，包括阿尔茨海默病（AD），帕金森病（PD）， 多发性硬化（MS）、肌萎缩侧索硬化（ALS）和亨廷顿病（HD）。但到 到2030年，五分之一的美国人将超过65岁，由于NDD主要发生在中年到晚年， 随着人口老龄化，预计发病率会飙升。这些情况突出表明， 开发目前缺乏的对NDD的有效治疗和治愈方法。虽然NDD不同， 他们的煽动机制，研究现在已经清楚地表明，存在的共同特点， 下游病理生理学，特别是失调的神经炎症系统的作用。的近期研究 人类和动物模型已经发现了一群小胶质细胞（疾病相关小胶质细胞，DAM）， 由不同的转录特征定义，并且在几个不同的NDD中保守。 有趣的是，DAM标签包括MS 4A基因的许多不同成员的上调 家族，许多全基因组关联研究已将其多态性与AD联系起来 （GWAS）。DAM中AD相关的MS 4A基因的上调引出了一个问题，即MS 4A是否 基因可能在NDD中发挥共同作用，它们共享DAM签名，此外，MS 4A是否 基因影响小胶质细胞在NDD背景下的功能特性。令人兴奋的是，我们的实验室发现， 在三种动物NDD模型（5XFAD、MAPT、SOD 1G 93 A）中，两种单独Ms 4a中的任一种缺陷的小鼠 家族成员表现出改善的疾病表型、延长的寿命和改善的 组织病理学疾病标志。因此，该提议将测试多个MS 4A在 在ALS小鼠模型中驱动病理学并调节小胶质细胞转录以及功能 对NDD环境的回应。为了检验这一假设，aim 1将调查同时缺失的影响 整个MS 4A基因家族在ALS中的作用。为此，我们已经产生了一种新的小鼠遗传试剂， 其中整个MS 4A基因簇被删除。将这些小鼠与SOD 1G 93 A ALS小鼠模型杂交 和ALS的病理特征，包括运动缺陷、寿命、小胶质细胞增生、神经元丢失和突触 将进行淘汰评估。目的2将研究MS 4A缺陷对转录和表达的影响。 从终末期SOD 1G 93 A小鼠分离的脊髓小胶质细胞的功能特性。具体来说，我将利用 单细胞RNA测序（scRNA-seq）与空间转录组学（MERFISH）串联，以评估 MS 4A缺失对DAM人群的影响。同时，我将研究如何MS 4A缺乏症在体内影响 吞噬作用的关键小胶质细胞功能总之，这些目标将提供基本的新见解， MS 4A在ALS中的作用，并有助于开发靶向MS 4A受体的治疗方法。