Understanding cleaved granulin production, protease inhibition and effects on protein homeostasis
Understanding cleaved granulin production, protease inhibition and effects on protein homeostasis
批准号:
10321541
负责人:
Aimee Kao
金额:
$35.53万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-01 至 2023-12-31
关键词:
Active SitesAffectAgeAlzheimer&aposs DiseaseAntibodiesArabidopsisAspartic EndopeptidasesBindingCaenorhabditis elegansCathepsinsCultured CellsCysteineDataDementiaDevelopmentDiseaseFoundationsFrontotemporal DementiaFrontotemporal Lobar DegenerationsGlycoproteinsGoalsHumanImpairmentIn VitroInflammationInterferometryKineticsKnowledgeLabelLeadLengthLifeLysosomal Storage DiseasesLysosomesMeasuresMissionModelingMolecularMutationNerve DegenerationNeurodegenerative DisordersNeuronsOutcomePGRN geneParkinson DiseasePathogenesisPatientsPeptide HydrolasesPeptidesPhylogenyPhysiologicalPlayPopulationProcessProductionPublic HealthRegulationReplacement TherapyResearchRiskRoleSpecificityStressSystemTestingToxic effectUnited States National Institutes of HealthWorkage relatedbasebiological adaptation to stressburden of illnessdriving forcegranulingranulin 2granulin 3improvedinnovationloss of function mutationmutation carrierneglectnew therapeutic targetnovelpleiotropismprotein TDP-43proteostasisreal time monitoringsensortoolwound healing
中文摘要
尽管最近取得了进展,但仍不清楚颗粒体蛋白前体缺乏如何导致
额颞叶变性 (FTLD) 并导致阿尔茨海默病 (AD)。颗粒体蛋白前体是
裂解成具有生物活性的颗粒体蛋白肽,在功能上对抗颗粒体蛋白前体全蛋白。许多人相信
颗粒体蛋白前体单倍体不足同样会消耗颗粒体蛋白前体和颗粒体蛋白水平,但这从未被证实过。
直接测量。关于将颗粒体蛋白前体裂解为
产生颗粒蛋白,这些裂解肽的正常功能以及颗粒蛋白对
蛋白质稳态和疾病。这项研究的长期目标是了解年龄相关性如何
蛋白质稳态的变化会影响 AD 和 FTLD 等神经退行性疾病的风险。目标
本应用的目的是了解使用 C 的颗粒蛋白的生产、功能和后果。
线虫、培养细胞和患者来源的生物样本。中心假设是年龄和
生理应激促进颗粒蛋白在内溶酶体系统中的释放,颗粒蛋白在此系统中结合
并抑制特定的溶酶体蛋白酶,最终损害神经元蛋白质稳态。这个
假设是基于申请人提供的大量初步数据,即颗粒蛋白生产
随着年龄和压力的增加,颗粒蛋白促进TDP-43积累并增强其毒性,而这些
富含半胱氨酸的肽可以结合并空间抑制溶酶体天冬氨酰蛋白酶的活性位点,
组织蛋白酶 D。这项工作的基本原理是了解颗粒体蛋白前体的产生和功能
颗粒蛋白对于安全靶向这些分子来治疗 FTLD 和其他疾病至关重要。
中心假设将通过三个具体目标进行检验:1)了解
颗粒蛋白,2) 确定颗粒蛋白抑制组织蛋白酶的特异性,3) 阐明
颗粒蛋白对蛋白质稳态的影响。拟议的研究在概念上具有创新性,因为它
试图直接暗示与年龄相关的颗粒体蛋白积累,而不是颗粒体蛋白前体或除了颗粒体蛋白前体之外
缺陷,作为与颗粒体蛋白前体突变相关的神经变性的驱动力。技术上也是如此
创新是因为开发了一种新型荧光颗粒体蛋白前体裂解传感器工具,使用了一种新的
一套抗人颗粒蛋白抗体以及 BioLayer 干涉测量 (BLI) 的应用,用于无标记、真实的
颗粒蛋白/组织蛋白酶相互作用动力学的时间监测。拟议的研究将做出重要贡献
有关颗粒蛋白的生产、特异性和功能后果的信息。这个贡献是
意义重大,因为它将提高对颗粒体蛋白前体单倍体不足如何导致 FTLD 的理解,
提供有关溶酶体蛋白酶正常调节的基本新知识,并奠定基础
为开发安全的颗粒体蛋白前体替代疗法奠定了基础。
英文摘要
Despite recent progress, it remains unclear how progranulin deficiency leads to development of
frontotemporal lobar degeneration (FTLD) and contributes to Alzheimer’s Disease (AD). Progranulin is
cleaved into bioactive granulin peptides that functionally oppose the progranulin holoprotein. Many believe
that progranulin haploinsufficiency equally depletes progranulin and granulin levels, yet this has never been
directly measured. Fundamental knowledge gaps also exist regarding proteases that cleave progranulin to
produce granulins, the normal function of these cleaved peptides and consequences of granulins on
protein homeostasis and disease. The long-term goal of this research is to understand how age-related
changes in protein homeostasis affect risk of neurodegenerative diseases like AD and FTLD. The objective
of this application is to understand the production, function and consequences of granulins using C.
elegans, cultured cells and patient-derived biospecimens. The central hypothesis is that age and
physiological stress promote the liberation of granulins in the endolysosomal system, where granulins bind
to and inhibit specific lysosomal proteases, ultimately impairing neuronal protein homeostasis. This
hypothesis is based on extensive preliminary data produced by the applicant that granulin production
increases with age and stress, granulins promote TDP-43 accumulation and enhance its toxicity, and these
cysteine-rich peptides can bind and sterically inhibit the active site of a lysosomal aspartyl protease,
cathepsin D. The rationale for this work is that understanding production and function of both progranulin
and granulins is critical to safely targeting these molecules in the treatment of FTLD and other diseases.
The central hypothesis will be tested through three specific aims: 1) understand the regulated production of
granulins, 2) determine the specificity profile of cathepsin inhibition by granulins, and 3) elucidate the
effects of granulins on protein homeostasis. The proposed research is conceptually innovative because it
seeks to directly implicate age-associated granulin accumulation, rather than or in addition to progranulin
deficiency, as a driving force in neurodegeneration related to progranulin mutations. It is also technically
innovative because of development of a novel fluorescent progranulin cleavage sensor tool, use of a new
set of anti-human granulin antibodies and application of BioLayer Interferometry (BLI) for label-free, real-
time monitoring of granulin/cathepsin interaction kinetics. The proposed research will contribute essential
information about the production, specificity and functional consequences of granulins. This contribution is
significant because it will improve understanding of how progranulin haploinsufficiency leads to FTLD,
provide fundamental new knowledge regarding the normal regulation of lysosomal proteases and lay the
foundation for development of safe progranulin replacement therapies.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3389/fnins.2020.602235
发表时间:
2020
期刊:
Frontiers in neuroscience
影响因子:
4.3
作者:
[Gururaj S, Sampognaro PJ, Argouarch AR, Kao AW]
通讯作者:
Kao AW
Diversity Supplement - Progranulin, Prosaposin and Lipid Biology in FTD
-
批准号:10734455
-
项目类别:
-
资助金额:$24.74万
-
财政年份:2023
-
负责人:Aimee Kao
-
依托单位:
Progranulin, Prosaposin and Lipid Biology in FTD
-
批准号:10464157
-
项目类别:
-
资助金额:$139.38万
-
财政年份:2022
-
负责人:Aimee Kao
-
依托单位:
Medical Scientist Training Program (T32 NRSA Training Grant)
-
批准号:10415874
-
项目类别:
-
资助金额:$171.11万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Core A: Administrative and Data Sharing Core
-
批准号:10493217
-
项目类别:
-
资助金额:$16.08万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Core A: Administrative and Data Sharing Core
-
批准号:10304090
-
项目类别:
-
资助金额:$20.33万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Medical Scientist Training Program (T32 NRSA Training Grant)
-
批准号:10634544
-
项目类别:
-
资助金额:$174.16万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Medical Scientist Training Program (T32 NRSA Training Grant)
-
批准号:10440129
-
项目类别:
-
资助金额:$5.38万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Medical Scientist Training Program (T32 NRSA Training Grant)
-
批准号:10655871
-
项目类别:
-
资助金额:$5.7万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Project 1: Tau metabolism: molecular chaperones, targeting and proteolysis
-
批准号:10304093
-
项目类别:
-
资助金额:$46.74万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Medical Scientist Training Program (T32 NRSA Training Grant)
-
批准号:10187949
-
项目类别:
-
资助金额:$161.29万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Project 1: Tau metabolism: molecular chaperones, targeting and proteolysis
-
批准号:10493227
-
项目类别:
-
资助金额:$46.41万
-
财政年份:2021
-
负责人:Aimee Kao
-
依托单位:
Systematic profiling of lysosomes with age to improve proteostasis in Alzheimer's
-
批准号:10180829
-
项目类别:
-
资助金额:$78.27万
-
财政年份:2018
-
负责人:Aimee Kao
-
依托单位:
Systematic profiling of lysosomes with age to improve proteostasis in Alzheimer's
-
批准号:10450686
-
项目类别:
-
资助金额:$78.27万
-
财政年份:2018
-
负责人:Aimee Kao
-
依托单位:
Systematic profiling of lysosomes with age to improve proteostasis in Alzheimer's
-
批准号:9789137
-
项目类别:
-
资助金额:$71.61万
-
财政年份:2018
-
负责人:Aimee Kao
-
依托单位:
Understanding cleaved granulin production, protease inhibition and effects on protein homeostasis
-
批准号:10088360
-
项目类别:
-
资助金额:$35.53万
-
财政年份:2018
-
负责人:Aimee Kao
-
依托单位:
Systematic profiling of lysosomes with age to improve proteostasis in Alzheimer's
-
批准号:9558641
-
项目类别:
-
资助金额:$50.34万
-
财政年份:2017
-
负责人:Aimee Kao
-
依托单位:
Understanding the molecular functions of progranulin and granulin in FTLD
-
批准号:9343071
-
项目类别:
-
资助金额:$34.74万
-
财政年份:2015
-
负责人:Aimee Kao
-
依托单位:
Understanding the molecular functions of progranulin and granulin in FTLD
-
批准号:9019872
-
项目类别:
-
资助金额:$33.45万
-
财政年份:2015
-
负责人:Aimee Kao
-
依托单位:
Understanding the molecular functions of progranulin and granulin in FTLD
-
批准号:9135550
-
项目类别:
-
资助金额:$34.48万
-
财政年份:2015
-
负责人:Aimee Kao
-
依托单位:
Genetic Approaches to Understanding Granulin Function
-
批准号:8725248
-
项目类别:
-
资助金额:$19.56万
-
财政年份:2013
-
负责人:Aimee Kao
-
依托单位:
海外基金