Genetic and environmental modifiers of pathology in amyotrophic lateral sclerosis

肌萎缩侧索硬化症病理学的遗传和环境调节剂

• 批准号: 10368010
• 负责人: Thor Stein
• 金额: --
• 依托单位: EDITH NOURSE ROGERS MEMORIAL VETERANS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368010
• 关键词: Address; Aging; Amyotrophic Lateral Sclerosis; Area; Atrophic; Autopsy; Axon; Behavior; Behavioral; Behavioral Symptoms; Biological Markers; Blast Injuries; CCL2 gene; CDC42 gene; Clinical; Cognitive; Collection; Craniocerebral Trauma; DNA; Data; Development; Diagnosis; Disease; Disease Progression; Drug Targeting; Frequencies; Frontotemporal Lobar Degenerations; Gene Expression; Genes; Genetic; Genetic Risk; Genotype; Gliosis; Goals; Impaired cognition; Individual; Inflammatory; Injury; Interferon Type II; Interleukin-1; Interleukin-4; Interleukin-6; Link; Logistic Regressions; Meta-Analysis; Methodology; Methods; Microglia; Molecular; Moods; Myelin; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Outcome; PGRN gene; Participant; Pathologic; Pathology; Pathway interactions; Pattern; Phenotype; Play; Population; Prefrontal Cortex; Prevalence; Prevention; Proteins; RNA; Recording of previous events; Research; Research Project Grants; Risk; Risk Factors; Role; Severities; Soldier; Symptoms; Synapses; TNF gene; Testing; Transcript; Translating; Traumatic Brain Injury; Variant; Veterans; amyotrophic lateral sclerosis therapy; chronic traumatic encephalopathy; cohort; comorbidity; contact sports; cost; cytokine; disease phenotype; drug discovery; experience; gene network; genetic risk factor; genome-wide; genomic variation; glial activation; gray matter; head impact; human subject; inflammatory modulation; mild traumatic brain injury; military veteran; neuroinflammation; neuron loss; neuropathology; novel; predict clinical outcome; preservation; progressive neurodegeneration; protein TDP-43; risk variant; targeted treatment; tau Proteins; transcriptome; transcriptome sequencing; translational approach; white matter

Traumatic brain injury (TBI) may be a risk factor for the development of amyotrophic lateral sclerosis (ALS). US military veterans have an increased frequency of ALS, and the veteran population has higher head injury prevalence than the comparable civilian population. Repetitive head impacts (RHI) are a form of mild TBI that can lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic traumatic encephalopathy (CTE). We have shown that ALS is a relatively frequent comorbidity in CTE (4) and that CTE occurs in a veteran population with ALS. Furthermore, genomic variation in TMEM106B may play an important role in both ALS and CTE disease progression. We hypothesize that TMEM106B is a modifier of disease presentation and severity in ALS and that TBI and RHI alter the associations of TMEM106B with pathology and clinical outcomes in CTE. Currently, there are no disease modifying treatments for ALS or CTE, and little is known about genetic modifiers of disease phenotype in ALS or CTE. This is largely because there has not been a systematic collection of participants with ALS, CTE, and both (ALS+CTE) until now. Our translational approach is to systematically address neurodegeneration in the world’s largest neuropathologically-confirmed autopsy cohort of ALS and CTE subjects on the DNA, RNA, and protein levels, with the goal of identifying novel genetic risk factors, biomarkers, and mechanisms that can be targeted for drug discovery. We have shown that compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation. Furthermore, we have demonstrated that variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in CTE. Variation in TMEM106B is also related to altered clinical outcomes in ALS, the development of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), and to progranulin (PRGN) levels and modulation of inflammatory pathways. Microglial activation is an early change in both ALS and CTE and may alter disease progression. Our hypothesis, based on our preliminary data, is that variants of TMEM106B have disease-specific associations with altered cytokines, pathology, and clinical disease progression in ALS and CTE. We further hypothesize that TMEM106B variation is associated with altered gene expression networks related to inflammatory pathways that predispose to worse pathological and clinical outcomes in ALS, CTE, and ALS+CTE. Our long-term goal is to uncover genetic and molecular mechanisms underlying the development of ALS and CTE in the setting of TBI. The immediate goal of this research project is to test the hypothesis that the TMEM106B risk allele leads to altered inflammatory gene expression and to determine TMEM106B-related disease modifying gene networks and neuroinflammatory markers that may serve as biomarkers to identify those individuals at risk for developing ALS and CTE and to uncover mechanisms that may be targeted for therapy. Overall, we aim to link a history of TBI to genetic, gene expression, and protein variation in human subjects with a definitive pathological diagnosis of ALS, CTE, and ALS+CTE.

外伤性脑损伤（TBI）可能是肌萎缩侧索硬化症（ALS）发展的危险因素。我们