Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease

构建集成免疫血管脑芯片作为阿尔茨海默病研究、药物筛选和治疗的平台

基本信息

项目摘要

Abstract Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost. While genetic studies are increasingly identifying polymorphisms that correlate with AD, there still is no clear picture of the molecular and cellular players and the extent to which each contributes to AD. The genetic and molecular complexity of AD and the lack of technology for experimentally unraveling it in human tissues create a bottleneck constricting the discovery of therapeutics and their successful translation into the clinic. Using human iPSCs we recently developed an in vitro blood-brain barrier (iBBB) and deployed it to discover mechanisms causing genetic predisposition to cerebral amyloid angiopathy (CAA). Identical to clinical studies, we found that APOE4, the strongest genetic risk factor for CAA and AD significantly increased amyloid deposition in our iBBB. The tractability of our engineered tissues then enabled dissection of the cellular causes of the disease. We found expression of APOE4 in pericytes alone was sufficient to increase cerebral vascular amyloid accumulation. Pinpointing the causal cells mediating CAA risk then enabled molecular and biochemical studies that established the underlying mechanism and revealed new therapeutic opportunities for mitigating genetic risk of CAA and potentially AD. Here, we will build upon our success, using the iBBB as a scaffold; we will incorporate neurons, oligodendrocytes, and microglia to generate a micro-integrated brain on a chip (miBrain-chip). In UG3 Aim1.1 we will establish miBrain-chips that represent healthy and diseased states of the human brain through iterative rounds of optimization that incorporate state-of-the-art biopolymers and engineering expertise from Robert Langer's lab at MIT. UG3 Aim1.2 will integrate and validate genetically encoded modulators and reporters of neuronal activity enabling the miBrain-chip to investigate how neuronal activity is influenced, and in turn, influences AD pathogenesis. UG3 Aim2 will model the pathological progression of AD in miBrain-chips across cohort of male and female sAD iPSC lines for which we have matched brains samples, clinical history, and genomic sequences. We will build computational models describing the transcriptional, cellular-dynamics and histological transformations that lead up to the end-states of post-mortem AD brains. These longitudinal pathological maps from genetically diverse healthy and sAD individuals will yield mechanistic insight into AD development and create a platform for discovery and efficacy screening of therapeutics. We hypothesize that the mechanisms underlying AD are significantly influenced by genetic variability. In UH3 we will establish the mechanisms underlying APOE4 pathogenesis (UH3 Aim1) and then ascertain the efficacy, toxicity, and therapeutic window of a panel of preclinical and clinical AD drugs using isogenic APOE3 and APOE4 miBrain-chips (UH3 Aim2). Our multimodal strategy will shed light on how genetic variation influences AD pathogenesis and therapeutic response, opening up new avenues for expeditious drug discovery and translation of effective therapeutics to the clinic.
摘要 阿尔茨海默病(AD)是一种使人衰弱的脑部疾病,具有惊人的人力和财力成本。而 遗传学研究越来越多地确定与AD相关的多态性,但仍然没有明确的描述 分子和细胞的球员和程度,每一个有助于AD。的遗传和 AD的分子复杂性和缺乏在人体组织中实验性地解开它的技术, 这是一个瓶颈,限制了治疗方法的发现和它们成功地转化为临床。使用 我们最近开发了一种体外血脑屏障(iBBB),并将其用于发现 导致大脑淀粉样血管病(CAA)遗传易感性的机制。与临床研究相同, 我们发现,CAA和AD最强的遗传危险因子APOE 4显著增加了淀粉样蛋白 在我们的iBBB中沉积。我们的工程组织的易处理性使我们能够解剖细胞原因 的疾病。我们发现APOE 4在周细胞中的单独表达足以增加脑血管 淀粉样蛋白积聚。精确定位介导CAA风险的因果细胞,然后使分子和 生物化学研究建立了潜在的机制,并揭示了新的治疗机会, 降低CAA和潜在AD的遗传风险。在这里,我们将建立在我们的成功,使用iBBB作为一个 支架;我们将纳入神经元,少突胶质细胞和小胶质细胞,以产生一个微整合的大脑上, 芯片(miBrain-chip)。在UG 3 Aim1.1中,我们将建立代表健康和患病的miBrain芯片 人类大脑的状态,通过迭代优化,包括最先进的生物聚合物 以及麻省理工学院罗伯特·兰格实验室的工程专业知识。UG 3 Aim1.2将整合并验证基因 编码的神经元活动的调节剂和报告者,使miBrain芯片能够研究神经元如何 活性受到影响,并反过来影响AD发病机制。UG 3 Aim 2将对病理性 miBrain芯片中的AD在男性和女性sAD iPSC系的队列中的进展, 匹配的大脑样本临床病史和基因组序列我们将建立计算模型 描述了导致最终状态的转录、细胞动力学和组织学转化 AD死后大脑的样本这些纵向病理图来自遗传多样的健康和sAD 个人将产生对AD发展的机制性见解,并为发现和疗效创造一个平台。 筛选治疗药物。我们推测,AD的潜在机制受到以下因素的显著影响: 遗传变异性在UH 3中,我们将建立APOE 4发病机制(UH 3 Aim 1), 然后确定一组临床前和临床AD药物的疗效、毒性和治疗窗口 使用等基因APOE 3和APOE 4 miBrain芯片(UH 3 Aim 2)。我们的多式联运战略将阐明如何 遗传变异影响AD发病机制和治疗反应,为治疗AD开辟了新的途径。 快速的药物发现和将有效的治疗方法转化为临床。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Joel William Blanchard其他文献

Joel William Blanchard的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Joel William Blanchard', 18)}}的其他基金

Understanding cell-type vulnerability and oxidative stress pathology in Parkinson's Disease using isogenic human dopaminergic neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
  • 批准号:
    10247522
  • 财政年份:
    2020
  • 资助金额:
    $ 225.9万
  • 项目类别:
Understanding cell-type vulnerability and oxidative stress pathology in Parkinson's Disease using isogenic human dopaminergic neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
  • 批准号:
    10458745
  • 财政年份:
    2020
  • 资助金额:
    $ 225.9万
  • 项目类别:
Understanding Cell-type Vulnerability and Oxidative Stress Pathology in Parkinson's Disease Using Isogenic Human Dopaminergic Neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
  • 批准号:
    10841881
  • 财政年份:
    2020
  • 资助金额:
    $ 225.9万
  • 项目类别:
Understanding Cell-type Vulnerability and Oxidative Stress Pathology in Parkinson's Disease Using Isogenic Human Dopaminergic Neurons
使用同基因人类多巴胺能神经元了解帕金森病的细胞类型脆弱性和氧化应激病理学
  • 批准号:
    10682394
  • 财政年份:
    2020
  • 资助金额:
    $ 225.9万
  • 项目类别:
Construction of an Integrated Immune - Vascular Brain - Chip as a Platform for the Study, Drug Screening, and Treatments of Alzheimer's Disease
构建集成免疫血管脑芯片作为阿尔茨海默病研究、药物筛选和治疗的平台
  • 批准号:
    10622543
  • 财政年份:
    2019
  • 资助金额:
    $ 225.9万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 225.9万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了