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Regulation of Extracellular Progranulin in the Brain

大脑中细胞外颗粒体蛋白前体的调节

基本信息

批准号：
10240644
负责人：
Andrew Emmett Arrant
金额：
$ 18.56万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240644
关键词：
Accounting Acute Address Alzheimer&apos s Disease Alzheimer&apos s disease risk Antibodies Antiinflammatory Effect Biology Blocking Antibodies Blood Brain Brain region Cell Culture Techniques Cell surface Cells Cerebrospinal Fluid Data Development Dominant Genetic Conditions Equilibrium Foundations Frontotemporal Dementia Future Genetic Genetic Polymorphism Genetic study Glycoproteins Golgi Apparatus Inflammation Infusion procedures Injury Link Lysosomes Measures Mediating Microdialysis Mus Mutation N-Methylaspartate Neuraxis Neurodegenerative Disorders Neurons Outcome Measure PGRN gene Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Patients Phase II Clinical Trials Physiological Physiology Picrotoxin Preclinical Testing Process Proteins Protocols documentation Receptor Signaling Regulation Rest Techniques Testing Tetrodotoxin Time Tissues Ventral Striatum Wild Type Mouse Work analog cell type enzyme activity experimental study extracellular in vivo insight loss of function loss of function mutation mouse model mutation carrier novel receptor sortilin therapy design uptake

项目摘要

Project Summary/Abstract Genetic studies indicate a link between low progranulin levels and neurodegenerative disease. Loss-of- function progranulin (GRN) mutations are one of the most common dominant genetic causes of frontotemporal dementia (FTD), accounting for around 5% of FTD cases. GRN polymorphisms are associated with increased risk for Alzheimer's disease (AD), FTD, and Parkinson's disease. Most pathogenic GRN mutations cause progranulin haploinsufficiency, and the best-known GRN polymorphism that increases risk of AD and FTD is associated with around 20% reduction of progranulin. Progranulin is secreted by multiple cell types throughout the body and is present in both blood and cerebrospinal fluid (CSF). Extracellular progranulin may interact with cell-surface signaling receptors to exert neurotrophic and anti-inflammatory effects. Extracellular progranulin is also taken up by cells and trafficked to lysosomes, where it enhances lysosomal enzyme activity. Progranulin haploinsufficiency is thought to drive FTD pathogenesis in GRN mutation carriers through loss of these beneficial effects. Progranulin-boosting therapies are under development to correct progranulin haploinsufficiency in GRN mutation carriers, either by increasing progranulin expression or reducing progranulin uptake. Both strategies should increase levels of extracellular progranulin, which could produce widespread correction of progranulin haploinsufficiency. However, very little is known about the regulation of extracellular progranulin in the brain. This is a major gap in the field that limits our ability to test progranulin- boosting therapies and investigate the physiologic functions of progranulin. Studies of progranulin in blood and CSF indicate differential regulation of extracellular progranulin levels in the periphery versus the central nervous system, highlighting the importance of studying extracellular progranulin in the brain. To address this need, we have adapted in vivo microdialysis to measure extracellular progranulin in the brain of mouse models. We propose to use this technique to investigate the mechanisms regulating brain extracellular progranulin levels. We hypothesize that brain extracellular progranulin levels are regulated by the balance between secretion and cellular uptake, and that these processes are dynamic, producing short-term fluctuations in extracellular progranulin levels. Progranulin is constitutively secreted, so in aim 1 we will test the hypothesis that progranulin expression is a major driver of secretion and thus extracellular progranulin levels. In aim 2 we will test the hypothesis that sortilin-mediated uptake is a major regulator of brain extracellular progranulin levels. We will conduct these experiments using a mouse-reactive analog of the sortilin-blocking antibody AL001, which is entering phase 2 clinical trials for FTD due to GRN mutations. In aim 3 we will test the hypothesis that neuronal activity increases brain extracellular progranulin levels. We anticipate that this work will lay the foundation for future studies of progranulin-boosting therapies and progranulin physiology.

项目总结/摘要遗传学研究表明低颗粒蛋白前体水平与神经退行性疾病之间存在联系。损失- 功能颗粒蛋白前体（GRN）突变是额颞叶萎缩最常见的显性遗传原因之一，痴呆（FTD），约占FTD病例的5%。GRN多态性与增加的阿尔茨海默病（AD）、FTD和帕金森病的风险。大多数致病性GRN突变导致颗粒蛋白前体单倍不足，最著名的GRN多态性，增加AD和FTD的风险是与颗粒蛋白前体减少约20%相关。颗粒蛋白前体由多种细胞类型分泌，它存在于血液和脑脊液（CSF）中。细胞外颗粒蛋白原可能与细胞表面信号受体发挥神经营养和抗炎作用。细胞外颗粒蛋白前体也被细胞吸收并运输到溶酶体，在那里它增强溶酶体酶活性。颗粒蛋白单倍不足被认为是通过这些基因的丢失来驱动GRN突变携带者的FTD发病机制。有益效果。颗粒蛋白前体增强疗法正在开发中，以纠正颗粒蛋白前体 GRN突变携带者中的单倍不足，通过增加颗粒蛋白前体表达或减少颗粒蛋白前体摄取这两种策略都应该增加细胞外颗粒蛋白前体的水平，广泛纠正颗粒蛋白前体单倍不足。然而，人们对监管知之甚少。细胞外颗粒蛋白前体这是该领域的一个主要空白，限制了我们测试颗粒蛋白前体的能力- 加强治疗和研究的生理功能的颗粒蛋白前体。血液和血液中颗粒蛋白前体的研究 CSF表明外周与中枢细胞外颗粒蛋白前体水平的差异调节神经系统，突出了研究细胞外颗粒蛋白前体在大脑中的重要性。为了解决这个根据需要，我们采用了体内微透析技术来测定小鼠脑细胞外颗粒蛋白前体模型我们建议使用这种技术来研究脑细胞外调节的机制颗粒蛋白前体水平。我们推测，脑细胞外颗粒蛋白前体水平是由平衡调节，之间的分泌和细胞摄取，这些过程是动态的，产生短期的细胞外颗粒蛋白前体水平的波动。颗粒蛋白前体是组成性分泌的，因此在目标1中，我们将测试假设颗粒蛋白前体表达是分泌的主要驱动力，因此细胞外颗粒蛋白前体水平。在目标2中，我们将测试这样的假设：分拣蛋白介导的吸收是脑细胞外的主要调节因子颗粒蛋白前体水平。我们将使用分拣蛋白阻断的小鼠反应性类似物进行这些实验。抗体AL 001，其由于GRN突变而进入FTD的2期临床试验。在目标3中，我们将测试神经元活动增加脑细胞外颗粒蛋白前体水平的假说。我们预计，这项工作将为今后的前颗粒蛋白增强疗法和前颗粒蛋白生理学研究奠定基础。