The combinatorial effects of familial mutations, oxidative stress, and aging on BBB dysfunction in Alzheimer's disease

家族突变、氧化应激和衰老对阿尔茨海默病 BBB 功能障碍的综合影响

• 批准号: 10464625
• 负责人: Tracy D. Chung
• 金额: $ 4.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464625
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Animals; Autopsy; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Categories; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Communication; Complex; Cues; Data; Data Set; Development; Disease; Disease Progression; Endothelial Cells; Etiology; Exposure to; Fellowship; Functional disorder; Future; Gene Expression; Gene set enrichment analysis; Goals; Human; Hydrogen Peroxide; Image; Immunohistochemistry; Impaired cognition; Impairment; Individual; Induced Mutation; Institutes; Institution; Intervention; Leadership; Libraries; Memory Loss; Mentorship; Microfabrication; Modeling; Molecular; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Onset of illness; Outcome; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Perfusion; Permeability; Pharmacology Study; Phenotype; Physiological; Prevention; Proteomics; Publishing; Research Training; Resolution; Role; Senile Plaques; Serum; Structural defect; Symptoms; Therapeutic; Tissue Engineering; Tissues; Toxin; Training; Transgenic Mice; Universities; Validation; Vascular Diseases; abeta deposition; age related; aged; base; blood-brain barrier disruption; blood-brain barrier function; brain cell; brain endothelial cell; brain tissue; career; combinatorial; design; disability; education resources; epidemiology study; experimental study; extracellular; familial Alzheimer disease; genetic signature; glucose transport; human old age (65+); imaging study; in vitro Model; in vivo; nanobiotechnology; occludin; presenilin-1; response; skills; solute; spatiotemporal; stem cell differentiation; stem cells; success; transcriptome sequencing; transcriptomics

Project Abstract Alzheimer’s disease is a disease of neurodegeneration and aging that affects millions of Americans, and is expected to impact millions more without further significant breakthroughs.1 However, much of the etiology and progression of Alzheimer’s is still unclear, especially given the complex interactions of many different molecular, cellular, and environmental cues that are correlated with phenotypic outcomes. An emerging focus in Alzheimer’s study is the role of the cerebrovasculature in the initiation, progression, and exacerbation of symptomatic disease.2-4 Disruption of the blood-brain barrier, which tightly controls any exchange between systemic circulation and brain tissue, has manifested in post-mortem and in vivo studies of late-stage Alzheimer’s disease as microbleeds, dysfunctional glucose transport, and impaired efflux of toxins;5 additional animal studies have indicated that some vascular dysfunction precedes neuronal degeneration in the progression of the disease.6, 7 Thus, to understand the drivers and progression of Alzheimer’s disease in hopes of identifying therapeutic breakpoints, the role of blood-brain barrier dysfunction must be investigated. To do so, we propose using a tissue-engineered model of the blood-brain barrier with high spatiotemporal resolution to assess its dysfunction under three key categories of perturbation associated with Alzheimer’s disease. These perturbations will span cell-intrinsic mutations associated with Alzheimer’s (APP(Swe) and PSEN(M146V)), extrinsic cues of oxidative stress (hydrogen peroxide exposure), and the systemic influence of aged blood components (exposure to aged vs. young human serum). We hypothesize that this combinatorial approach will best recapitulate human BBB phenotype in Alzheimer’s, and allow for modular study of each contributor. These perturbations will be compared transcriptomically, proteomically, and functionally. Transcriptomic changes will be studied through bulk RNA-sequencing and gene set enrichment analysis to highlight similarities to published human datasets, identify hallmark pathways that are impacted by Alzheimer’s cues, and motivate functional assay design for further validation in the tissue-engineered model. Proteomic and functional assessments include changes to barrier function, cell identity, and validation of pathways implicated by transcriptomic analysis. This study will provide a deeper understanding of the role of the blood- brain barrier in Alzheimer’s progression and emphasize candidate targets for future intervention. This project and related research training will be conducted under the guidance of Dr. Peter Searson at Johns Hopkins University and the Institute for Nanobiotechnology. Skills including functional assay design, stem cell differentiation, microfabrication, and RNA-sequencing analysis will be supported by the educational resources available within the institution. Additional goals of the fellowship training period will incorporate professional development for future career success, with an emphasis on communication, mentorship, and leadership skills.

项目摘要 阿尔茨海默氏病是一种神经变性和衰老的疾病，会影响数百万美国人，并且是 预计不会影响数百万的情况而没有进一步的突破。1然而，许多病因 阿尔茨海默氏症的进展仍不清楚，特别是考虑到许多不同的复杂相互作用 与表型结果相关的分子，细胞和环境线索。新兴的重点 在阿尔茨海默氏症的研究中，脑血管造成的作用在主动性，进展和加剧中的作用 有症状性疾病。2-4血脑屏障的破坏，该障碍紧密控制 系统性圆圈和脑组织已在后期的验尸和体内研究中表现出来 阿尔茨海默氏病作为微孔，功能失调的葡萄糖转运和毒素外排受损；另外5个 动物研究表明，一些血管功能障碍先于神经元变性 第6卷，第7章，以了解阿尔茨海默氏病的驱动力和进展 必须研究识别治疗断裂点的希望，必须研究血脑屏障功能障碍的作用。 为此，我们建议使用具有高时空的血脑屏障的组织工程模型 在与阿尔茨海默氏症相关的三个关键类别下评估其功能障碍的决议 疾病。这些扰动将跨越与阿尔茨海默氏症相关的细胞中性突变（App（SWE）和 PSEN（M146V）），氧化应激的外部提示（过氧化氢暴露）以及全身影响 老化的血液成分（暴露于老年人与年轻的人血清）。我们假设这个组合 方法最好概括阿尔茨海默氏症中的人类BBB表型，并允许对每种人进行模块化研究 贡献者。这些扰动将通过转录，蛋白质组学和功能进行比较。 转录组的变化将通过大量的RNA测序和基因集富集分析进行研究 突出显示与已发布的人类数据集的相似性，确定受阿尔茨海默氏症影响的标志性途径 提示和融合的功能测定设计，以在组织工程模型中进行进一步验证。蛋白质组学 功能评估包括对屏障功能的变化，细胞身份以及途径的验证 通过转录组分析实施。这项研究将对血液的作用有更深入的了解 阿尔茨海默氏症的进展和应急候选目标的脑屏障，以将来干预。 该项目和相关研究培训将在约翰斯的彼得·西尔森（Peter Searson）博士的指导下进行 霍普金斯大学和纳米元学研究所。技能在内，包括功能分析设计，干细胞 教育资源将支持差异化，微作业和RNA序列分析 在机构内可用。奖学金培训期的其他目标将纳入专业 发展未来职业成功的发展，重点是沟通，指导和领导技能。