Targeting neuroinflammation in AD with novel CX3CR1 agonists

使用新型 CX3CR1 激动剂靶向 AD 中的神经炎症

基本信息

批准号：
10158381
负责人：
Kevin Ron Nash
金额：
$ 67.71万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158381
关键词：
APP-PS1 Address Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapy Aminoquinolines Amyloid beta-Protein Amyloid deposition Animal Disease Models Animal Model Animals Anti-Inflammatory Agents Atrophic Autopsy Behavioral Binding Proteins Bioavailable Biochemical Biological Assay Biological Markers Brain CX3CL1 gene Catalogs Characteristics Chemicals Chemistry Data Dementia Deposition Development Disease Disease Progression Disease model Dose Drug Kinetics Ensure Fractalkine Funding Opportunities Goals Growth Factor Health Human Impaired cognition Inflammation Inflammatory Innate Immune System Lead Maximum Tolerated Dose Measures Mediating Medical Membrane Microglia Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Oral Outcome Measure PTPRC gene Parkinson Disease Pathologic Pathology Pathway interactions Penetration Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Plasma Play Property Proteins Proteomics Resistance Resources Rodent Role Route Series Signal Transduction Solubility TNF gene Tauopathies Testing Therapeutic Tissues Transgenic Mice Work analog candidate marker cerebral atrophy chemokine drug discovery effective therapy efficacy study extracellular fractalkine receptor high throughput screening improved in vitro Bioassay in vivo lead optimization meetings mouse model mutant nervous system disorder neuroinflammation neuron loss new therapeutic target novel novel therapeutics overexpression pre-clinical preclinical study receptor scaffold small molecule success targeted treatment tau Proteins tau phosphorylation tool transcriptome sequencing

APP-PS1 Address Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapy Aminoquinolines Amyloid beta-Protein Amyloid deposition Animal Disease Models Animal Model Animals Anti-Inflammatory Agents Atrophic Autopsy Behavioral Binding Proteins Bioavailable Biochemical Biological Assay Biological Markers Brain CX3CL1 gene Catalogs Characteristics Chemicals Chemistry Data Dementia Deposition Development Disease Disease Progression Disease model Dose Drug Kinetics Ensure Fractalkine Funding Opportunities Goals Growth Factor Health Human Impaired cognition Inflammation Inflammatory Innate Immune System Lead Maximum Tolerated Dose Measures Mediating Medical Membrane Microglia Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Oral Outcome Measure PTPRC gene Parkinson Disease Pathologic Pathology Pathway interactions Penetration Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Plasma Play Property Proteins Proteomics Resistance Resources Rodent Role Route Series Signal Transduction Solubility TNF gene Tauopathies Testing Therapeutic Tissues Transgenic Mice Work analog candidate marker cerebral atrophy chemokine drug discovery effective therapy efficacy study extracellular fractalkine receptor high throughput screening improved in vitro Bioassay in vivo lead optimization meetings mouse model mutant nervous system disorder neuroinflammation neuron loss new therapeutic target novel novel therapeutics overexpression pre-clinical preclinical study receptor scaffold small molecule success targeted treatment tau Proteins tau phosphorylation tool transcriptome sequencing

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项目摘要

PROJECT SUMMARY Fractalkine protein (FKN, CX3CL1) suppresses microglial activation leading to decreased neurodegeneration in a number of neurological disorders, including Alzheimer's disease (AD). In AD, a large reduction in FKN has been observed in postmortem cortical tissue. We have studied FKN and its role in neurodegeneration extensively, and we have demonstrated a beneficial effect of FKN in multiple neurodegenerative disease models. Our work demonstrates that overexpression of a soluble form of FKN (sFKN) decreases tau pathology in Tg4510 mice. More importantly, we observed that sFKN significantly reduces brain atrophy and neuron loss in these mice. In Parkinson's disease (PD) mouse models, overexpression of sFKN, but not a cleavage-resistant, insoluble mutant FKN, reduces disease pathology and neuron loss. Positive activity with soluble versus membrane-bound FKN suggests that a soluble molecule has the potential to activate the receptor and achieve neuroprotective effects. These observations prompted the hypothesis that the FKN pathway could be exploited as a therapeutic approach to treat AD. High-throughput screening produced a series of chemical scaffolds that are novel small molecule agonists of CX3CR1 suitable for further optimization through this funding opportunity. The lead compound is potent and highly selective, and has been shown to reduce LPS-mediated activation of microglia. Here, we propose to develop orally bioavailable potent CX3CR1 agonist compounds suitable for use as chemical probes. This campaign leverages the unique resources of Sanford Burnham Prebys and USF Health. Chemistry efforts will refine the current lead compound to improve potency and selectivity, and enhance the compound's drug-like properties. These efforts are supported by a robust testing funnel consisting of cellular and biochemical assays of CX3CR1 signaling, as well as appropriate counter-screens. The physicochemical and pharmacological properties of the compounds will be optimized, followed by pharmacokinetic studies in rodents. We will test for target engagement and efficacy in the AD animal models, in which we will identify at least one CX3CR1 agonist with potent efficacy in vivo.

项目摘要分面蛋白（FKN，CX3CL1）抑制小胶质细胞激活导致降低许多神经系统疾病的神经变性，包括阿尔茨海默氏病（AD）。在广告中，一个大在死后皮质组织中已经观察到FKN的降低。我们研究了FKN及其在神经变性广泛，我们已经证明了FKN在多个神经退行性疾病模型。我们的工作表明，FKN可溶性形式的过表达（SFKN）降低了TG4510小鼠的tau病理。更重要的是，我们观察到SFKN显着减少了这些小鼠的脑萎缩和神经元丧失。在帕金森氏病（PD）小鼠模型中 SFKN，但不是抗切割的，不溶性的突变体FKN，可以减少疾病病理和神经元丧失。积极的可溶性与膜结合的FKN的活性表明可溶性分子具有激活的潜力受体并获得神经保护作用。这些观察结果促使了FKN的假设途径可以被用作治疗AD的治疗方法。高通量筛选产生了一系列新型小分子激动剂的化学支架 CX3CR1适用于通过此资助机会进一步优化。铅化合物有效，高度选择性，已被证明可以减少LPS介导的小胶质细胞激活。在这里，我们建议开发口服可生物可用的有效CX3CR1激动剂化合物，适合用作化学探针。这竞选利用Sanford Burnham Prebys和USF Health的独特资源。化学努力将优化当前的铅化合物以提高效力和选择性，并增强该化合物的类似药物样特性。这些努力得到了由细胞和生化测定的强大测试漏斗的支持 CX3CR1信号传导以及适当的反屏幕。物理化学和药理化合物的性能将被优化，然后在啮齿动物中进行药代动力学研究。我们将测试 AD动物模型中的目标参与和功效，我们将至少确定一个CX3CR1激动剂在体内有效的功效。