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Role of Sarm1 in TBI-accentuated C9orf72 Frontotemporal Dementia

Sarm1 在 TBI 加重的 C9orf72 额颞叶痴呆中的作用

基本信息

批准号：
10646932
负责人：
Nils Henninger
金额：
$ 25.13万
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：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646932
关键词：
ALS patients Ablation Acceleration Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Astrocytes Attenuated Axon Bacterial Artificial Chromosomes Behavior Behavior assessment Behavioral Biological Assay C9ORF72 Categories Cells Clinical Data Defect Dendritic Spines Denervation Deposition Dipeptides Disease Disease Progression Environmental Risk Factor Epidemiology Event Evolution Fluorescent in Situ Hybridization Frontotemporal Dementia Functional disorder Genes Genetic Genetic Risk Glaucoma Goals Histologic Immunohistochemistry Impaired cognition Individual Inherited Injury Interleukin-1 beta Intervention Investigation Link Metabolic Microglia Microscopic Modeling Molecular Morphology Motor Motor Cortex Motor Neurons Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Neuronal Injury Neurons Nicotinamide adenine dinucleotide Onset of illness Pathologic Pathology Pathway interactions Patients Penetration Peripheral Nerves Peripheral Nervous System Diseases Persons Process RNA Reporting Research Risk Risk Factors Role Sterility Stimulus Stress Temporal Lobe Testing Time Transcript Transgenic Organisms Translating Traumatic Brain Injury Variant Western Blotting axon injury axonal degeneration c9FTD/ALS cognitive testing density effective therapy epidemiologic data experimental study frontal lobe frontotemporal lobar dementia amyotrophic lateral sclerosis improved insight mild traumatic brain injury molecular pathology motor impairment mouse model nervous system disorder neuroinflammation neuropathology neurotoxic preservation programs protein TDP-43 protein activation response sham surgery sporadic amyotrophic lateral sclerosis therapeutic target

项目摘要

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases without available therapy. Epidemiological data suggest that traumatic brain injury (TBI) is a risk factor for ALS and FTD; TBI, ALS, and FTD share several pathological findings, including neuronal and axonal degeneration, neuroinflammation, and mislocalization of TDP-43. Axonal pathology, an early event after TBI, promotes TDP-43 dysregulation and may serve as a trigger for neurodegenerative processes. Axon loss can be driven by a genetically encoded program governed by the axon destruction factor SARM1, rendering it an attractive target for treating many neurological diseases. We and others have reported that SARM1 clearly promotes TBI-associated neurodegeneration and a role for SARM1 has also been proposed in ALS/FTD. Since most cases of ALS/FTD are sporadic, involving multiple risk factors, we will test the hypothesis that the adverse role of SARM1 in ALS/FTD is revealed in mice using a “two-hit model” (TBI combined with a C9orf72 ALS/FTD gene defect) that reflect the combined risks of a harmful environmental stimulus with genetic risk in sporadic ALS/FTD patients. The most common cause of dominantly inherited ALS and FTD is a hexanucleotide repeat expansion (HRE) in the C9orf72 gene (c9ALS/FTD). However, it remains to be established whether (1) TBI can trigger events that accelerate pathology and clinical disease in HRE carriers, and (2) whether there are interventions to blunt the impact of TBI and attenuate adverse neuropathological events. Our pilot data provide proof-of-concept that repetitive mild TBI (rTBI) causes extensive neuronal and axonal loss and persistent neuroinflammation at 12 months after injury in a transgenic C9orf72 (C9BACtg/tg) mouse model. In Aim1 we will conduct a time-course experiment in non-transgenic and transgenic C9BACtg/tg mice to quantify pathology in frontal and temporal cortices for up to 12 months after rTBI or sham surgery. We will use immunohistochemistry markers for neurons, axons, microglia, astroglia, and TDP-43; WB and qPCR for TDP-43 expression; cytometric bead array for interleukin-1β expression; fluorescence in situ hybridization for RNA foci; and Meso Scale Discovery assay for dipeptide repeats as markers of c9ALS/FTD pathology after rTBI or sham surgery. A battery of motor and cognitive tests will be used to assess behavioral deficits. These experiments will test the hypothesis that following rTBI c9ALS/FTD mice will manifest exaggerated behavioral, microscopic, and molecular pathology, and accelerated disease-onset. In Aim2 we will use our established colony of C9BACtg/tgxSarm1-/- mice, to conduct a time- course experiment analogous to Aim1 to ascertain if genetic ablation of Sarm1 attenuates neurodegeneration and behavioral deficits following rTBI. These experiments will test the hypothesis that following rTBI, behavioral, microscopic, and molecular pathology will be attenuated in c9ALS/FTD mice by inactivation of Sarm1. Together, these experiments will illuminate mechanisms underlying c9ALS/FTD after rTBI by identifying cellular and molecular response pathways and providing insights into principles governing the interplay between TDP-43 and neurodegeneration in c9ALS/FTD. Our studies may also define SARM1 as a therapeutic target to mitigate the devasting consequences of this and other TBI- associated neurodegenerative diseases such as Alzheimer's disease (AD) and related dementias (ADRD).

肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是严重的神经退行性疾病没有可用的治疗。流行病学数据表明，创伤性脑损伤（TBI）是ALS和FTD的危险因素; TBI、ALS和FTD共有几种病理学发现，包括神经元和轴突变性、神经炎症，和TDP-43的错误定位。轴突病理学，TBI后的早期事件，促进TDP-43失调，可能有助于作为神经退化过程的触发器。轴突的缺失可以由一个基因编码的程序驱动，轴突破坏因子SARM 1，使其成为治疗许多神经系统疾病的有吸引力的目标。我们和其他人已经报道了SARM 1明显促进TBI相关的神经变性，并且SARM 1的作用也已经被证实。在ALS/FTD中提出。由于大多数ALS/FTD病例是散发性的，涉及多种风险因素，我们将检测假设SARM 1在ALS/FTD中的不利作用在小鼠中使用“两次打击模型”（TBI联合 C9 orf 72 ALS/FTD基因缺陷），反映了有害环境刺激与遗传风险的综合风险，散发性ALS/FTD患者。显性遗传ALS和FTD最常见的原因是六核苷酸重复 C9 orf 72基因扩增（HRE）（c9 ALS/FTD）。然而，还有待确定的是（1）TBI是否可以触发加速HRE携带者的病理和临床疾病的事件，以及（2）是否有干预措施来减弱HRE携带者的病理和临床疾病。 TBI影响和减弱不良神经病理学事件。我们的试点数据提供了概念验证，重复性轻度 TBI（rTBI）在损伤后12个月引起广泛的神经元和轴突损失以及持续的神经炎症，转基因C9 orf 72（C9 BACtg/tg）小鼠模型。在目标1中，我们将在非转基因和转基因C9 BACtg/tg小鼠，以量化rTBI或假手术后长达12个月的额叶和颞叶皮质病理学手术我们将使用神经元、轴突、小胶质细胞、星形胶质细胞和TDP-43的免疫组织化学标记物; WB和qPCR TDP-43表达;流式细胞仪微球阵列检测白细胞介素-1 β表达;荧光原位杂交检测RNA 病灶;以及用于二肽重复序列的Meso Scale Discovery测定，作为rTBI或假手术后c9 ALS/FTD病理学的标志物。一系列运动和认知测试将用于评估行为缺陷。这些实验将检验这个假设 rTBI后c9 ALS/FTD小鼠将表现出过度的行为、显微镜和分子病理学，并且加速发病。在目标2中，我们将使用我们建立的C9 BACtg/tgxSarm 1-/-小鼠群体，进行时间- 类似于Aim 1的课程实验，以确定Sarm 1的基因消融是否会减弱神经变性和行为 rTBI后的缺陷。这些实验将检验以下假设：rTBI后，行为、微观和在c9 ALS/FTD小鼠中，通过灭活Sarm 1可减弱分子病理学。这些实验将通过识别细胞和分子反应途径阐明rTBI后c9 ALS/FTD的潜在机制，提供了关于TDP-43和c9 ALS/FTD中神经变性之间相互作用的原理的见解。我们研究也可以将SARM 1定义为治疗靶点，以减轻这种和其他TBI的破坏性后果。相关的神经退行性疾病，如阿尔茨海默病（AD）和相关痴呆（ADRD）。