Vascular MicroRNA-212 in CAA and Alzheimer's disease

CAA 和阿尔茨海默病中的血管 MicroRNA-212

基本信息

批准号：
10807420
负责人：
Silvia Fossati
金额：
$ 39.39万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2023-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10807420
关键词：
AD transgenic mice Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloidosis Autopsy Binding Sites Biological Biological Assay Biological Models Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Budgets Candidate Disease Gene Caspase Cell Death Cell Survival Cell physiology Cells Cellular Stress Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Characteristics Co-Immunoprecipitations Collaborations Data Deposition Development Diagnostic Disease Disease Progression Down-Regulation Elderly Electrical Resistance Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Equilibrium Essential Genes Exhibits Failure Functional disorder Funding Gatekeeping Gene Expression Gene Proteins Genes Goals Grant Hemorrhage Homologous Gene Human Hypoxia Image Immunohistochemistry Impaired cognition In Situ In Situ Hybridization In Vitro Ischemia Measures Mediating Mediator Methods MicroRNAs Modeling Mus Mutagenesis Neurodegenerative Disorders Neurons Northern Blotting Oligonucleotides Pathogenesis Pathologic Pathology Pathway interactions Permeability Phenotype Physiological Play Preparation Proteins Quantitative Reverse Transcriptase PCR Regulation Regulator Genes Reporter Research Research Personnel Risk Role Secure Severity of illness Site Small RNA Stress Stroke System TNFRSF10A gene TNFRSF10B gene Testing Tg2576 Therapeutic Toxic effect Transgenic Mice United States National Institutes of Health Untranslated RNA Variant Western Blotting Work abeta deposition abeta toxicity beta amyloid pathology blood-brain barrier disruption blood-brain barrier function blood-brain barrier permeabilization brain endothelial cell cell injury cerebrovascular clinically relevant endothelial dysfunction experimental study gene network improved in vivo mRNA sequencing monolayer mouse model neurovascular neurovascular unit novel overexpression response therapeutic miRNA therapeutically effective translational study vascular cognitive impairment and dementia vascular contributions

AD transgenic mice Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloidosis Autopsy Binding Sites Biological Biological Assay Biological Models Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Budgets Candidate Disease Gene Caspase Cell Death Cell Survival Cell physiology Cells Cellular Stress Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Characteristics Co-Immunoprecipitations Collaborations Data Deposition Development Diagnostic Disease Disease Progression Down-Regulation Elderly Electrical Resistance Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Equilibrium Essential Genes Exhibits Failure Functional disorder Funding Gatekeeping Gene Expression Gene Proteins Genes Goals Grant Hemorrhage Homologous Gene Human Hypoxia Image Immunohistochemistry Impaired cognition In Situ In Situ Hybridization In Vitro Ischemia Measures Mediating Mediator Methods MicroRNAs Modeling Mus Mutagenesis Neurodegenerative Disorders Neurons Northern Blotting Oligonucleotides Pathogenesis Pathologic Pathology Pathway interactions Permeability Phenotype Physiological Play Preparation Proteins Quantitative Reverse Transcriptase PCR Regulation Regulator Genes Reporter Research Research Personnel Risk Role Secure Severity of illness Site Small RNA Stress Stroke System TNFRSF10A gene TNFRSF10B gene Testing Tg2576 Therapeutic Toxic effect Transgenic Mice United States National Institutes of Health Untranslated RNA Variant Western Blotting Work abeta deposition abeta toxicity beta amyloid pathology blood-brain barrier disruption blood-brain barrier function blood-brain barrier permeabilization brain endothelial cell cell injury cerebrovascular clinically relevant endothelial dysfunction experimental study gene network improved in vivo mRNA sequencing monolayer mouse model neurovascular neurovascular unit novel overexpression response therapeutic miRNA therapeutically effective translational study vascular cognitive impairment and dementia vascular contributions

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项目摘要

Summary Pathological changes in the brain vasculature contribute to Alzheimer’s disease (AD) and AD-related dementias (ADRD). Amyloid β (Aβ)-mediated endothelial damage may lead to microbleeds, stroke, hypoxia, alterations in cerebral blood flow and malfunction of the entire neurovascular unit, contributing to cognitive impairment. Micro- RNAs (miRNAs) regulate gene expression and protein levels, bearing functions essential for cell survival and functioning in normal and stress conditions. MiRNAs are highly enriched in the brain and play critical roles in development and disease. While the vascular contributions to AD pathology are well recognized, the changes in miRNA expression in endothelial cells in the AD/ADRD brain are still mostly unexplored. We propose to assess the effect of amyloid challenge on miRNA regulation in cerebral endothelial cells, addressing the overarching hypothesis that the Aβ peptide, a known causative factor of AD, triggers endothelial miRNA alterations, the most significant being miR-212 downregulation, contributing to the blood-brain barrier (BBB) failure and neurovascular dysfunction characteristic of AD. Our specific goal is to demonstrate the hypothesis that the Aβ peptide promotes cerebrovascular dysfunction and BBB failure via endothelial miR-212. Using human primary and immortalized endothelial cells, purified cerebral vessels from transgenic mice with vascular amyloidosis, and post-mortem brain vasculature from human AD cases with vascular Aβ and pure cerebral amyloid angiopathy (CAA) cases, we aim to test the following hypotheses that: Aim 1: toxic Aβ species specifically reduce miR-212 in cerebral endothelial cells. Aim 2: MiR-212 targets modulate endothelial cell stress/death genes and pathways. Aim 3: miR-212 loss disrupts BBB function. This project will benefit from the combined expertise and collaboration of two PIs specialized respectively in vascular/endothelial dysfunction in CAA and AD and miRNA research in AD and ADRD. This study will allow us to clarify the role of specific vascular miRNAs and, by re-establishing their correct equilibrium, restore gene expression and biological networks in the cerebral vasculature. The long-term goal of the proposed research will be the development of novel miRNA-focused therapeutic strategies against neurovascular dysfunction in AD and related dementias.

概括脑脉管系统的病理变化有助于阿尔茨海默氏病（AD）和广告相关的痴呆症（ADRD）。淀粉样β（Aβ）介导的内皮损伤可能会导致微粒，中风，缺氧，变化整个神经血管单元的脑血流和故障，导致认知障碍。微- RNA（miRNA）调节基因表达和蛋白质水平，对细胞存活至关重要的功能在正常和应力条件下发挥作用。 miRNA在大脑中高度丰富，并在发展与疾病。尽管对AD病理的血管贡献得到了充分的认可，但变化的变化 AD/ADRD大脑中内皮细胞中的miRNA表达仍然大多是出乎意料的。我们建议评估淀粉样蛋白挑战对脑内皮细胞中miRNA调节的影响，解决了总体假设，即Aβ肽是AD的已知灾难性因素，触发了内皮 miRNA改变，最重要的是miR-212下调，导致血脑屏障（BBB）AD的衰竭和神经血管功能障碍特征。我们的具体目标是证明假设Aβ肽通过内皮促进脑血管功能障碍和BBB衰竭 mir-212。使用人类原发性和永生的内皮细胞，来自转基因小鼠的纯化脑视频血管淀粉样变性，以及来自血管Aβ和纯粹的人类AD病例的死亡后脑血管脑淀粉样血管病（CAA）病例，我们旨在测试以下假设：AIM 1：有毒Aβ物种目标2：miR-212靶标调节内皮细胞应激/死亡基因和途径。 AIM 3：miR-212损失破坏了BBB功能。该项目将分别从两个PIS专业知识和合作中受益 CAA中的血管/内皮功能障碍，AD和ADRD中的AD和miRNA研究。这项研究将使我们为了阐明特定的血管miRNA的作用，并通过重新建立其正确的等效物来恢复基因脑脉管系统中的表达和生物网络。拟议研究的长期目标将成为针对AD和相关痴呆症。