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Region-Specific Vulnerability of the Lewy Body Dementia's Brain

路易体痴呆症大脑的区域特异性脆弱性

基本信息

批准号：
10651712
负责人：
Tae-In Kam
金额：
$ 75.37万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651712
关键词：
Affect Alzheimer&apos s Disease Amino Acids Animal Model Area Astrocytes Biochemical Bioinformatics Biological Models Braak&apos s hypothesis Brain Brain region Cells Cerebellum Cognitive Complex Data Dementia Development Disease Dissection Event Exhibits Exposure to Functional disorder Goals Heterogeneity Hippocampus Human Individual Investigation Label Lewy Bodies Lewy Body Dementia Lewy neurites Limbic System Messenger RNA Microdissection Microglia Modeling Molecular Neocortex Nerve Degeneration Neurites Neurobehavioral Manifestations Neurodegenerative Disorders Neurons Parkinsonian Disorders Pathogenesis Pathologic Pathway interactions Pattern Physiology Population Process Proteins Proteome Research Personnel Role Signal Pathway Technology Validation alpha synuclein brain tissue cell behavior cell type entorhinal cortex in vivo insight motor symptom mouse model neocortical neurodegenerative dementia neuron loss novel physical separation single cell analysis synucleinopathy transcriptome

项目摘要

REGION-SPECIFIC VULNERABILITY OF THE LEWY BODY DEMENTIA’S BRAIN PROJECT SUMMARY Lewy Body Dementia (LBD) is a progressive neurodegenerative disorder characterized by aggregation of the α- synuclein (α-syn) into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). This form of dementia belongs to a class of neurodegenerative diseases termed “synucleinopathies.” LBD is the most common neurodegenerative dementia after Alzheimer’s disease. In LBD, dementia usually proceeds to the onset of parkinsonian motor symptoms with neurobehavioral symptoms that may be accompanied by both cognitive and motoric dysfunction. While various misfolded oligomers, primarily constituted of α-syn, are associated with the development of dementia along with neuronal loss, there is still insufficient understanding of the pathogenesis process. Especially, particular brain areas such as the limbic system and neocortex are more vulnerable than other regions. Researchers have considered that the answer to this question will provide a key clue to understanding the pathogenesis mechanism. Inter-cellular crosstalk of neurons, microglia, and astrocytes results in complex physiologies and cellular behaviors, potentially leading to neuronal loss. Moreover, there is brain region-specific heterogeneity in cellular populations of neurons, microglia, and astrocytes that can contribute to the region-specific vulnerability of the LBD brain. Therefore, information on cell-type-specific and single-cell- specific proteome and transcriptome over multiple brain regions is indispensable for understanding this complex mechanism. To study this complex mechanism, the selection of the right aminal model that best recapitulates the human LBD pathogenesis process is crucial. The mouse model that recapitulates the Braak hypothesis would serve as the best animal model and we recently have generated this mouse model (gut-brain α-syn model) successfully by injecting α-syn to the gut. To study the regional vulnerability of LBD using the mouse model, we propose 1) to study region- and cell-type-specific proteome of the brain of the gut-brain α-syn model using BONCAT and xMD, 2) to study region- and single-cell-specific transcriptome of the brain of the gut-brain α-syn model using HiF-snRNAseq, 3) to perform integrative bioinformatic analysis and validate the affected pathways found in the mouse models using the human brain. Cell-type-specific proteome analysis and single-cell transcriptome analyses over multiple brain regions of the gut-brain α-syn model proposed in this application will enable us to identify region- and cell-type-specific signaling pathways that are involved in region-specific vulnerabilities to pathological α-syn. This novel information will contribute to a better understanding of LBD pathogenesis. Furthermore, these approaches can be expanded to studying pathogenesis mechanisms of other neurodegenerative diseases.

路易体痴呆患者大脑的区域特异性脆弱性项目摘要路易体痴呆（Lewy Body Dementia，LBD）是一种进行性神经退行性疾病，其特征在于α- 突触核蛋白（α-syn）进入称为路易体（LB）和路易神经突（LN）的细胞内内含物。这种形式的痴呆属于一类称为“突触核蛋白病”的神经变性疾病。LBD是最阿尔茨海默病后常见的神经退行性痴呆在LBD中，痴呆通常在发病前进行，帕金森病运动症状与神经行为症状，可能伴随着两个认知和运动功能障碍虽然各种错误折叠的低聚物，主要由α-syn组成，虽然痴呆的发展沿着神经元的丧失，但对发病机制的认识仍然不足过程特别是，某些大脑区域，如边缘系统和新皮层，比其他区域更容易受到伤害。其他地区。研究人员认为，这个问题的答案将提供一个关键线索，了解发病机制。神经元、小胶质细胞和星形胶质细胞的细胞间串扰结果在复杂的生理和细胞行为中，可能导致神经元损失。此外，还有大脑神经元、小胶质细胞和星形胶质细胞的细胞群体中的区域特异性异质性， LBD大脑的特定区域脆弱性。因此，关于细胞类型特异性和单细胞- 在多个脑区的特定蛋白质组和转录组是理解这一复杂的必不可少的机制为了研究这种复杂的机制，选择最能概括的右胺模型，人类LBD发病过程是至关重要的。再现布拉克假说的小鼠模型将作为最好的动物模型，我们最近建立了这种小鼠模型（肠-脑α-syn模型）成功地将α-syn注射到肠道。为了使用小鼠模型研究LBD的区域脆弱性，我们建议1）研究肠-脑α-syn模型脑的区域和细胞类型特异性蛋白质组， BONCAT和xMD，2）研究肠脑α-syn脑的区域特异性和单细胞特异性转录组，使用HiF-snRNAseq的模型，3）进行综合生物信息学分析并验证受影响的途径在使用人脑的小鼠模型中发现。细胞类型特异性蛋白质组分析和单细胞本申请中提出的肠-脑α-syn模型的多个脑区域的转录组分析将使我们能够识别区域和细胞类型特异性信号通路，参与区域特异性对病态α-syn的脆弱性。这些新的信息将有助于更好地了解LBD 发病机制此外，这些方法可以扩展到研究其他疾病的发病机制。神经退行性疾病