Elucidating the role of CHI3L1/YKL-40 in Alzheimer's disease

阐明 CHI3L1/YKL-40 在阿尔茨海默病中的作用

基本信息

批准号：
10901027
负责人：
Yu-Wen Alvin Huang
金额：
$ 38.57万
依托单位：
BROWN UNIVERSITY
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：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901027
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Alzheimer’s disease biomarker Amyloidosis Anti-Inflammatory Agents Astrocytes Binding Biological Biological Assay Biological Models Biology Brain CHI3L1 gene Cell Surface Receptors Chitinase Clinical Collaborations Complex Data Development Disease Elements Feedback Funding Gliosis Goals Health Human Immune response In Vitro Induction of Apoptosis Inflammatory Inflammatory Response Knowledge Laboratories Lentivirus Macrophage Mediating Methodology Methods Microglia Mission Mutation NF-kappa B Natural Immunity Nature Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Neurons Neurophysiology - biologic function Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Peripheral Phenotype Process Property Proteins Public Health Publishing Reagent Receptor Signaling Research Research Personnel Role Signal Induction Signal Pathway Signal Transduction Signaling Molecule Stress System Testing Therapeutic Tissues United States National Institutes of Health Universities Work brain cell cell type disability early detection biomarkers glial activation human stem cells improved induced pluripotent stem cell inflammatory modulation inhibitor injury and repair mutant neural neuroinflammation neuroprotection neurotoxic neurotoxicity presenilin-1 prevent receptor receptor binding receptor for advanced glycation endproducts response stem cell model therapy development translational potential translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Chitinase-3-like protein 1 (CHI3L1/YKL-40) is well known as a powerful biomarker for early detection of neuroinflammation and Alzheimer’s disease (AD). While in peripheral tissues CHI3L1 has been well characterized to regulate a wide range of immune and inflammatory responses, how it acts in the brain in the process of neuroinflammation and AD development remains largely unknown. Recent evidence shows that CHI3L1 is primarily secreted by activated astrocytes to signal a neurotoxic inflammatory response across major brain cell types. The dynamic interactions between microglia, astrocytes and neurons are among the major drivers for the inflammatory neurotoxicity underlying development of AD pathology. Disentangling such intricate cellular cross-talk in human neural systems, and the role of CHI3L1 in this process, thus signifies a critical need for developing therapeutics for AD and relevant neurodegenerative disorders. The long-term goal of my laboratory is to understand the pathogenic determinants of neurodegeneration to inform treatments for AD. Using human stem cell-based methodologies, the overall objectives in this application are: i) to define the signaling mechanism whereby CHI3L1 governs glial activation and neurodegeneration; and ii) to develop the translational potential of these signaling mechanisms to prevent neuronal damage in AD. Supported by our preliminary data, our central hypothesis is that astrocyte-derived CHI3L1 functions as a signaling molecule to mediate inflammatory responses in a cell type-specific manner – promoting neuronal degeneration and regulating microglial inflammatory profiles. We also hypothesize that silencing neuronal CHI3L1 signaling will dampen neurotoxicity and ameliorate AD pathogenesis. We propose to exploit iPSC-based pure and mixed human neural cultures (microglia, astrocytes and neurons) to anatomize the inter-cellular interactions and rigorously test our hypotheses. Three specific aims will be pursued to attain the overall objectives: in Aim 1, we will identify the neuronal CHI3L1 receptor and downstream signaling pathway that convey the detrimental effects of CHI3L1 on neurodegeneration in AD, using human neuronal cultures derived from isogenic control and multiple AD mutant iPSC lines (from NIH-funded iNDI); in Aim 2, we will define the CHI3L1-modulated inflammatory properties of microglia in AD, by control and AD mutant iPSC-derived human microglia; in Aim 3, we will decide the mechanism of CHI3L1 function in astrocyte-microglial interactions for neurodegeneration in AD, aided by a reductionist method to dissect the neuroprotective element out of the neuron-glial and glia-glial interactions of neuroinflammation - the tricultures of human microglia, astrocytes and neurons generated from control and AD mutant iPSCs. Our expected outcomes are to define an essential CHI3L1 signaling mechanism governing neuroinflammation underlying AD neurodegeneration. This work will elucidate the biology of a prominent AD biomarker, which will define a new path for AD/ADRD treatment and thus constitutes a significant positive impact.

项目概要/摘要几丁质酶 3 样蛋白 1 (CHI3L1/YKL-40) 是众所周知的早期检测的强大生物标志物而在外周组织中，CHI3L1 则表现良好。其特点是调节广泛的免疫和炎症反应，它如何在大脑中发挥作用神经炎症和 AD 发展的过程在很大程度上仍然未知。 CHI3L1 主要由激活的星形胶质细胞分泌，以发出跨主要神经毒性炎症反应的信号小胶质细胞、星形胶质细胞和神经元之间的动态相互作用是主要的脑细胞类型。解开这种复杂的病理学发展背后的炎症神经毒性的驱动因素。人类神经系统中的细胞串扰，以及 CHI3L1 在此过程中的作用，因此表明迫切需要开发 AD 和相关神经退行性疾病的治疗方法是我的长期目标。实验室的目的是了解神经退行性变的致病决定因素，为 AD 的治疗提供信息。基于人类干细胞的方法学，本申请的总体目标是：i) 定义信号传导 CHI3L1 控制神经胶质细胞激活和神经变性的机制；以及 ii) 发展翻译；我们的初步数据支持这些信号机制预防 AD 神经损伤的潜力，我们的中心假设是星形胶质细胞衍生的 CHI3L1 作为信号分子来介导以细胞类型特异性方式产生炎症反应——促进神经元变性和调节我们还发现，沉默神经元 CHI3L1 信号传导会抑制小胶质细胞炎症。我们建议开发基于 iPSC 的纯人类神经细胞和混合人类神经细胞。培养物（小胶质细胞、星形胶质细胞和神经元）来解剖细胞间相互作用并严格测试我们的为了实现总体目标，我们将追求三个具体目标：在目标 1 中，我们将确定神经元 CHI3L1 受体和传达 CHI3L1 对健康的不良影响的下游信号通路 AD 中的神经变性，使用来自同基因对照和多个 AD 突变体的人类神经元培养物 iPSC 系（来自 NIH 资助的 iNDI）；在目标 2 中，我们将定义 CHI3L1 调节的炎症特性 AD 中的小胶质细胞，通过目标 3 中的对照和 AD 突变体 iPSC 衍生的人类小胶质细胞，我们将确定其机制；在还原论的帮助下，CHI3L1 在 AD 神经变性的星形胶质细胞-小胶质细胞相互作用中的功能从神经元-胶质细胞和胶质细胞-胶质细胞相互作用中剖析神经保护元件的方法神经炎症 - 对照和 AD 产生的人类小胶质细胞、星形胶质细胞和神经元的三培养物我们的预期结果是定义一个重要的 CHI3L1 信号传导机制。 AD 神经变性背后的神经炎症这项工作将阐明 AD 的生物学特性。生物标志物，将为 AD/ADRD 治疗开辟新途径，从而产生重大积极影响。