The Neuronal Effect of CHI3L1 in Neuroinflammation & Alzheimer's Disease

CHI3L1 在神经炎症中的神经元作用

• 批准号: 10679915
• 负责人: Kevin C Connolly
• 金额: $ 4.77万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679915
• 关键词: AD transgenic mice; Address; Adopted; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apoptosis; Astrocytes; Award; Binding; Biology; Brain; CHI3L1 gene; Cause of Death; Cell Surface Receptors; Cells; Central Nervous System; Cerebrospinal Fluid; Characteristics; Chitinase; Data; Dedications; Diagnosis; Disease; Enterobacteria phage P1 Cre recombinase; Event; Funding; Future; Genes; Genetic; Genetic Transcription; Gliosis; Goals; Growth; Hippocampus; Human; Immune; Immune signaling; Immunity; Impairment; In Vitro; Inflammatory; Injections; Intervention; Knock-out; Laboratories; LoxP-flanked allele; Lung; Lung diseases; Measurement; Measures; Mediating; Medical; Methods; Molecular; Mouse Strains; Nerve Degeneration; Neurites; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neuroglia; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathologic; Pathway interactions; Peripheral; Phosphorylation; Play; Pluripotent Stem Cells; Prevention strategy; Process; Proteins; Quantitative Reverse Transcriptase PCR; RNA Interference; Receptor Gene; Recombinants; Reporting; Research; Research Personnel; Research Training; Resources; Role; Scientist; Senile Plaques; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Structure of parenchyma of lung; Synapses; System; TIE gene; Testing; Tissues; Training; Transcript; Transgenic Mice; United States; Western Blotting; age related neurodegeneration; career; cell type; combat; conditional knockout; confocal imaging; experimental study; extracellular; in vivo; induced pluripotent stem cell; mouse model; mutant; neuroinflammation; neuron apoptosis; neuron loss; neurotoxic; neurotoxicity; neurotransmission; presenilin-1; protein expression; receptor; response; secretase; skills; stem cells; success; synaptic function; targeted treatment; tau-1; transcriptomics

PROJECT SUMMARY One in three Americans will be diagnosed with Alzheimer’s disease (AD) if no new prevention and intervention strategies are developed. The pathological hallmarks of AD include accumulation extracellular amyloid plaques consisting of amyloid beta (Aβ), processed from amyloid precursor protein (APP), and intracellular neurofibrillary tangles comprised of phospho-tau. These features are proceeded and precipitated by a wide range of intra- and inter-cellular functions, with derailed neuroinflammation being among the earliest manifestations in human brains. Of note, Chitinase-3-like protein 1 (CHI3L1, or YKL-40), an inflammatory protein mainly secreted by reactive astrocytes in the brain, has been documented to be a powerful AD biomarker, and its cerebrospinal fluid (CSF) level has recently been reported to be potentially the first disease indicator. However, how it functions in the brain and influences neuroinflammation and AD pathogenesis remains to be elucidated. In contrast, in peripheral tissues such as in the pulmonary system, CHI3L1 has been well characterized as an immune signaling molecule that controls many aspects of inflammatory processes via specific cell surface receptors and downstream signaling pathways. Teaming up with leading expertise in CHI3L1 biology in lung diseases, the Huang laboratory has gathered evidence showing that CHI3L1 is expressed more abundantly in astrocytes from AD brains and can mediate the inflammatory signaling and cellular responses as in the periphery. Supported by my own preliminary data, my central hypothesis is that CHI3L1 secreted by activated astrocytes engages a neuronal receptor and triggers a signaling cascade in neurons that contributes to the inflammatory neurotoxicity and leads to neurodegeneration and relevant AD features. My overall objective here is to define a neuronal signaling mechanism whereby CHI3L1 regulates glia-derived neuroinflammatory response and the resultant neurodegeneration. By using human neurons generated from pluripotent stem cells in single cultures and a Chi3l1-floxed mouse strain, I propose to pursue two specific aims in order to test my hypothesis and achieve the objective. In Aim 1, I will identify the CHI3L1 receptor and downstream signaling pathway in stem cell-derived human neurons in vitro. In Aim 2, I will determine the effects of CHI3L1 expression on inflammatory neurotoxicity in vivo in transgenic mouse brains with conditional Chi3l1 knockout and expression of AD pathology. My expected outcome is to elucidate an essential signaling function of CHI3L1 in neurons in response to neuroinflammatory stress. My results will reveal a mechanistic role CHI3L1 plays in the brain, departing from being merely a biomarker for AD and neuroinflammation. There will be a positive impact as my findings can be used in targeted therapeutics to combat AD. Finally, the primary responsibility of a F31 awardee is, in lieu of performing experiments, to prepare him/herself for future success in research. With this regard, my major goal of award period is to leverage the rich resources at Brown and execute a rigorous training plan that will impart to me the skills, ingenuity and experimental acumen necessary for growth into an independent investigator.

项目摘要 如果没有新的预防和干预措施，三分之一的美国人将被诊断患有阿尔茨海默病（AD） 制定了战略。AD的病理特征是细胞外淀粉样斑块的积累 由淀粉样前体蛋白（APP）加工而成的β淀粉样蛋白（Aβ）和细胞内神经胶质细胞组成。 由磷酸化tau组成的缠结。这些特征是由一系列广泛的内部和外部因素推动和沉淀的。 细胞间的功能，与出轨的神经炎症是人类最早的表现之一， 大脑值得注意的是，几丁质酶-3样蛋白1（CHI 3L 1，或YKL-40），一种主要由炎症细胞分泌的炎性蛋白， 已被证明是一种强大的AD生物标志物，其脑脊液 (CSF)最近有报道说，这一水平可能是第一个疾病指标。然而，它如何在 脑和影响神经炎症和AD发病机制仍有待阐明。而反观 在外周组织如肺系统中，CHI 3L 1已被充分表征为免疫信号传导因子。 通过特定细胞表面受体控制炎症过程许多方面的分子， 下游信号通路。与CHI 3L 1生物学在肺部疾病方面的领先专业知识合作， Huang实验室收集的证据表明，CHI 3L 1在星形胶质细胞中表达更丰富， AD的大脑和可以介导的炎症信号和细胞反应，如在周边。支持 根据我自己的初步数据，我的中心假设是，由激活的星形胶质细胞分泌的CHI 3L 1与一个细胞因子的作用有关。 神经元受体，并触发神经元中的信号级联反应，导致炎症性神经毒性 并导致神经变性和相关的AD特征。我的总体目标是定义一个神经元 CHI 3L 1调节神经胶质源性神经炎症反应的信号传导机制 神经变性通过在单一培养物中使用由多能干细胞产生的人类神经元， Chi 3l 1-floxed小鼠品系，我建议追求两个具体的目标，以检验我的假设，并实现 objective.在目标1中，我将确定干细胞衍生的细胞中的CHI 3L 1受体和下游信号通路。 体外培养的人类神经元在目标2中，我将确定CHI 3L 1表达对炎症神经毒性的影响 在具有条件性Chi 3l 1敲除和AD病理学表达的转基因小鼠脑中的体内。我 预期的结果是阐明了神经元中CHI 3L 1的基本信号传导功能， 神经炎性应激我的研究结果将揭示CHI 3L 1在大脑中发挥的机械作用， 仅仅是AD和神经炎症的生物标志物。我的发现会产生积极的影响 用于治疗AD的靶向治疗。最后，F31获奖者的主要责任是， 进行实验，为他/她将来在研究中取得成功做好准备。在这方面，我的主要目标 奖励期的目的是利用布朗大学的丰富资源，执行严格的培训计划， 对我来说，成长为一名独立调查员所必需的技能、独创性和实验敏锐性。