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The Role of Chromogranin A in Tauopathy

嗜铬粒蛋白 A 在 Tau 蛋白病中的作用

基本信息

批准号：
10214077
负责人：
Xu Chen
金额：
$ 43.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214077
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid beta-Protein Area Biochemical Process Brain Cardiovascular system Cells Chromogranin A Chronic Clinical Trials Cognition Complex Cultured Cells Cytoplasmic Granules Cytotoxin Data Dense Core Vesicle Deposition Development Disease Endocrine Event Failure Frontotemporal Dementia Funding Genes Glycoproteins Goals Health Heterozygote Homeostasis Homozygote Hormones Human Hybrids Impairment In Vitro Industrialization Inflammation Inflammatory Insulin Insulin Resistance Interleukin-1 beta Investigation Knock-out Knowledge Laboratories Link Longevity Metabolic stress Metabolism Microglia Mission Modeling Mus Mutation NF-kappa B Nerve Degeneration Neuroendocrine Cell Neurofibrillary Tangles Neurons Neurotransmitters Outcome Pathogenesis Pathologic Pathology Pathway interactions Peptides Pharmaceutical Preparations Physiology Play Population Published Comment Publishing Reporting Research Rest Risk Role Senile Plaques Signal Transduction Synapses Synaptic Vesicles System Tauopathies Testing Therapeutic Tissues Toll-like receptors Toxic effect Traction Transgenic Mice Vision Wild Type Mouse Work base cognitive function effective therapy exhaustion experimental study extracellular heart function human old age (65+)hyperphosphorylated tau in vivo insulin sensitivity metabolic phenotype monoamine mouse model neuroinflammation novel therapeutics overexpression prevent response secretory protein success synergism tau Proteins tau aggregation tau mutation therapeutic target

项目摘要

Project Summary Tauopathies including Alzheimer's Disease (AD) and frontotemporal dementia (FTD) affect a third of the world population aged over 65. To cope with this health crisis, industrial and academic laboratories have been trying to develop drugs. These efforts have resulted in hundreds of clinical trials, but the success has been limited to only slowing the disease by a handful. The failure points our lack of knowledge of how these diseases set off. Therefore, there is a need to better understand the biochemical processes in the early stage of these diseases. It is possible that regulatory imbalances brought by many factors rendering these diseases highly heterogeneous. To address these complex issues, it is critical to identify new factors contributing to the development of tauopathies. This proposal will determine if a secretory protein factor, chromogranin A (CgA), plays any role in tauopathies. CgA is an acidic glycoprotein synthesized and stored in hormone storage granules of endocrine cells and neurons acting as a regulator of neurotransmitter. It plays an important role in maintaining tissue homeostasis, inflammation, and insulin sensitivity. CgA concentration was reported to be high in the CSF of AD patients and was frequently observed in Aβ plaques surrounded by activated microglia and stimulates the release of cytotoxins. These previous reports, however, are based on in vitro experiments in cultured cells and no real progress has been made to understand CgA's role in AD in vivo. Moreover, whether CgA plays a role in tau pathogenesis is completely unknown. Three research groups with expertise in tauopathy, CgA physiology, and inflammation will work together to investigate if and how CgA affects cognition, neuroinflammation, and metabolism of PS19 transgenic mice. We have gathered preliminary information showing that i) PS19 mice are insulin-resistant; ii) CgA is overexpressed in PS19 and iii) an inflammatory pathway is activated in PS19 mice brain. Our data along with published reports led us to hypothesize that overexpression of CgA is responsible for i) metabolic stress, ii) neuroinflammation and iii) neurotransmitter imbalance. These abnormalities are intimately associated with heightened pathological tau accumulation resulting in the full-blown disease. To test our hypothesis, we will generate PS19/Chga-/- and PS19/Chga-/+ mice, and determine if the depletion of CgA ameliorates neurodegeneration by comparing i) pathological tau accumulation and propagation, ii) neuroinflammation, iii) cognitive function, and iv) metabolic phenotype and longevity, in these and age- matched PS19/Chga+/+ (PS19) and non-transgenic/Chga+/+ (wild type) mice.

项目摘要包括阿尔茨海默病(AD)和额颞部痴呆(FTD)在内的各种疾病影响着三分之一的 65岁以上的世界人口。为了应对这场健康危机，工业和学术实验室一直在努力研发药物。这些努力已经导致了数百项临床试验，但成功的仅限于将疾病延缓一小部分。这一失败表明我们缺乏对这些疾病爆发了。因此，有必要更好地了解早期的生化过程。这些疾病。有可能是许多因素造成的监管失衡导致了这些疾病高度异质性。要解决这些复杂的问题，关键是要找出促成这些问题的新因素牛顿病症的发展。这项提议将确定一种分泌蛋白因子--嗜铬粒素A(CGA)是否在紧张症。CgA是一种合成并储存在内分泌激素储存颗粒中的酸性糖蛋白。细胞和神经元作为神经递质的调节器。它在维持组织中起着重要的作用动态平衡、炎症和胰岛素敏感性。据报道，脑脊液中的CgA浓度很高。 AD患者，常见于被激活的小胶质细胞和刺激物包围的β斑块中细胞毒素的释放。然而，这些先前的报告是基于体外培养的细胞，在了解CGA在体内AD中的作用方面还没有取得真正的进展。此外，CGA是否在tau的发病机制中起到的作用完全未知。三个在直肠疗法、CGA生理学和炎症方面具有专业知识的研究小组将开展工作共同研究CGA是否以及如何影响PS19的认知、神经炎症和代谢转基因小鼠。我们已经收集的初步信息表明：i)PS19小鼠是胰岛素抵抗的； Ii)CgA在PS19中过表达；III)在PS19小鼠脑内激活了一条炎症通路。我们的数据与已发表的报告一起，我们提出假设，CGA的过度表达是导致I)代谢的原因应激，ii)神经炎症和iii)神经递质失衡。这些异常现象密切相关伴随着病理性tau的高度积聚，导致疾病的全面发展。测试我们的假设，我们将产生PS19/CHGA-/-和PS19/CHGA-/+小鼠，并确定CGA是否耗尽通过比较i)病理性tau蓄积和繁殖，ii)改善神经退化神经炎症，III)认知功能，以及IV)代谢表型和寿命，在这些和年龄- 将PS19/CHGA+/+(PS19)和非转基因/CHGA+/+(野生型)小鼠配对。