Screening for enhancers of secreted clusterin (sCLU) and evaluation in AD models
分泌型凝聚素 (sCLU) 增强子的筛选和 AD 模型的评估
基本信息
- 批准号:10195566
- 负责人:
- 金额:$ 42.34万
- 依托单位:
- 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:2021-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1AddressAdverse effectsAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer’s disease biomarkerAmyloid beta-ProteinApoptoticBinding ProteinsBiological AssayBiological AvailabilityBiological MarkersBiological ProcessBrainCardiovascular DiseasesCell Culture TechniquesCell DeathCell LineCell SurvivalCellsCellular Stress ResponseCentral Nervous System DiseasesConsensusCytoprotectionDevelopmentDevicesDiseaseDisease ProgressionDrug KineticsEffectivenessEnhancersEvaluationFailureFunctional disorderFutureGlioblastomaGoalsHalf-LifeHippocampus (Brain)HomeostasisHumanImmunoassayImpaired cognitionIn VitroInduced pluripotent stem cell derived neuronsInflammationLate Onset Alzheimer DiseaseLeadLibrariesLiquid substanceLiteratureMalignant NeoplasmsMass Spectrum AnalysisMeasuresMetabolicMitochondriaMolecularMolecular ChaperonesMolecular TargetNatureNerve DegenerationNeuronsOralOxidative RegulationOxidative StressPathologyPermeabilityPharmaceutical PreparationsPharmacologyPhosphotransferasesPhotoaffinity LabelsPreclinical TestingPredispositionPropertyProtein IsoformsProteinsPublic HealthResearchRoleSenile PlaquesSignal PathwaySignal TransductionSliceSolubilityStressTestingTestisTherapeuticToxic effectTreatment Efficacyabeta depositionbasedrug candidateeffectiveness evaluationefficacy testingexperimental studyextracellulargenetic risk factorgenetic variantglycogen synthase kinase 3 betahigh throughput screeninghyperphosphorylated tauimmunoregulationin vivoinduced pluripotent stem cellinnovationinstrumentlipid transportmouse modelnerve stem cellneuroblastoma cellnovelnovel therapeutic interventionprogramsproteotoxicityscreeningsmall moleculesulfated glycoprotein 2tau aggregationtau phosphorylationtau-1treatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
This proposal provides a unique opportunity to identify isoform-specific modulators of clusterin (CLU) and
evaluate its role in Alzheimer's disease (AD). Clusterin, also known as apolipoprotein J (Apo J) is a protein
originally identified in 1979. Several CLU gene variants are associated with AD and the SNP rs11136000C is
the third strongest genetic risk factor for Late Onset Alzheimer's disease (LOAD). There is evidence that
enhancing brain levels of sCLU will slow or reverse various molecular mechanisms underlying onset of the AD
pathophysiology. This is based on studies that show sCLU promoting the clearance of disease-causing
amyloid beta (Aβ) plaques, while reducing cellular stress responses such as oxidative stress and inflammation
known to lead to increased kinase activity such as GSK-3β and increased hyperphosphorylated tau involved in
progression of AD. Interestingly, the CLU gene variants that confer increased susceptibility to LOAD also
reduce sCLU levels and result in increased Aβ deposition and tau neurofibrillary tangles and faster cognitive
decline relative to non-carriers. In this proposal a comprehensive research program will be undertaken to
identify potent, brain permeable, small molecules that increase levels of sCLU and modulate biomarkers in AD
models. This will be accomplished using high throughput screening (HTS) to identify `hits' with potent sCLU
enhancing ability, drug-like properties, brain permeability in pharmacokinetics (PK) analyses to guide
compound selection for further testing and mechanism-of-action (MOA) studies in iPSC derived neurons and
ex-vivo models of AD. In Aim1 we will screen for compounds that increase extracellular concentrations of
sCLU. UCLA's large compound library will be screened by using fully automated liquid handling devices and
analytical instruments to identify molecules that increase sCLU levels. For these experiments, sensitive and
readily formattable AlphaLISA based immunoassays will be optimized to detect different CLU isoforms. In
Aim2, we would conduct in-vitro ADME/T testing and in-vivo pharmacokinetics (PK) analyses to guide hit
selection including determination of sCLU enhancing potency, characterizing the physiochemical properties
including solubility, brain permeability and metabolic stability of candidate sCLU enhancing compounds. In
Aim3, we would conduct testing in induced pluripotent stem cells (iPSCs) derived neurons and ex-vivo brain
slices. The goal is to evaluate the effectiveness of sCLU enhancers with sufficient oral brain bioavailability and
half-life in AD patient-derived neurons as well as in ex-vivo organotypic brain slice cultures from the
hippocampi of an AD mouse model. In Aim4, we would identify molecular targets and cell signaling pathways
affected by prioritized hits. MOA studies involving target identification by photoaffinity-labeling/purification as
well as global and phosphoproteome analyses will be accomplished using state-of-the-art mass spectrometry.
Using these approaches, we will identify molecular targets of our sCLU enhancing compounds to identify novel
mechanisms involved in regulating brain sCLU levels in AD.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Varghese John其他文献
Varghese John的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Varghese John', 18)}}的其他基金
Evaluating the p-Tau inhibition and neuroprotective effects of sAPPalpha using brain permeable small molecules
使用脑通透性小分子评估 sAPPalpha 的 p-Tau 抑制和神经保护作用
- 批准号:
10522638 - 财政年份:2022
- 资助金额:
$ 42.34万 - 项目类别:
Screening for Compounds that Lower Intracellular Alpha-Synuclein Levels
筛选降低细胞内 α-突触核蛋白水平的化合物
- 批准号:
10218979 - 财政年份:2021
- 资助金额:
$ 42.34万 - 项目类别:
Small molecule mimetics of Humanin that normalize neuronal p-Akt as novel therapeutics for AD
护脑素小分子模拟物可使神经元 p-Akt 正常化,作为 AD 的新型疗法
- 批准号:
10810521 - 财政年份:2021
- 资助金额:
$ 42.34万 - 项目类别:
Small molecule mimetics of Humanin that normalize neuronal p-Akt as novel therapeutics for AD
护脑素小分子模拟物可使神经元 p-Akt 正常化,作为 AD 的新型疗法
- 批准号:
10211023 - 财政年份:2021
- 资助金额:
$ 42.34万 - 项目类别:
Screening for Compounds that Lower Intracellular Alpha-Synuclein Levels
筛选降低细胞内 α-突触核蛋白水平的化合物
- 批准号:
10524695 - 财政年份:2021
- 资助金额:
$ 42.34万 - 项目类别:
ApoE4-targeted therapeutics that normalize SirT1
使 SirT1 正常化的 ApoE4 靶向疗法
- 批准号:
9914435 - 财政年份:2019
- 资助金额:
$ 42.34万 - 项目类别:
ApoE4-targeted therapeutics that normalize SirT1
使 SirT1 正常化的 ApoE4 靶向疗法
- 批准号:
8988211 - 财政年份:2015
- 资助金额:
$ 42.34万 - 项目类别:
ApoE4-targeted therapeutics that normalize SirT1
使 SirT1 正常化的 ApoE4 靶向疗法
- 批准号:
9231359 - 财政年份:2015
- 资助金额:
$ 42.34万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 42.34万 - 项目类别:
Research Grant














{{item.name}}会员




