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
基本信息
- 批准号:10810521
- 负责人:
- 金额:$ 27.48万
- 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:AccelerationAdministrative SupplementAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAmino AcidsAmyloid beta-ProteinAnimalsArea Under CurveAutopsyAwardBinding ProteinsBiologicalBiological AssayBrainCardiovascular DiseasesCellsCharacteristicsCodeDataDiabetes MellitusDiseaseDoseDrug KineticsElderlyEnhancersEnzyme-Linked Immunosorbent AssayEuthanasiaEvaluationFutureGenderGrantHalf-LifeHourHumanIL6ST geneImpaired cognitionIn VitroLeftLibrariesLinkMethodsMicrosomesMitochondriaMusN-MethylaspartateNeuroblastomaNeuronsNoiseOccipital lobeOralPeptidesPermeabilityPharmaceutical PreparationsPharmacodynamicsPlasmaPlasma ProteinsPlayPropertyReportingResearchRoleRouteSamplingSiblingsSignal TransductionTestingTimeTissuesToxic effectValidationWorkanalogbrain tissuecandidate selectiondosageevaluation/testingexperimental studygenome wide association studyhigh throughput screeninghumaninin vivoinduced pluripotent stem cellmimeticsmitochondrial genomemouse modelneuroblastoma cellneuroprotectionnovel therapeuticsparent grantpharmacokinetics and pharmacodynamicsscale upscreeningsmall moleculesubcutaneoustherapeutic candidate
项目摘要
ABSTRACT (Supplement)
Humanin (HN), a 24-amino acid mitochondrial-derived peptide from the occipital lobe of postmortem sporadic
AD patient brain tissue [1] is a neuroprotective peptide that could protect neurons from Aβ-related and NMDA-
induced toxicity [2]. A decrease in the endogenous HN plasma level with age has been reported [3], and
decreased HN levels has been linked to cognitive decline during aging. The identification of a SNP (rs2854128)
using mitochondrial GWAS in the HN-coding region of the mitochondrial genome from a large sample of older
adults further supports the role of HN and its circulating levels with accelerated cognitive decline [4]. The
availability of high throughput screening (HTS) formattable assays, allow for screening to identify small molecules
that can enhance HN expression and its levels in AD models. In the parent grant we completed screening for
small molecules that act as humanin (HN) mimetics and have identified validated hits that increase both the p-
gp130 and p-Akt levels in neuronal cells. Further analoging, testing and evaluation of these mimetics are ongoing
following the path outlined in the grant. The availability of new assays to assess levels of HN peptide itself in
vitro and in tissue has presented the opportunity to also identify small molecules that enhance HN levels. Our
preliminary data using this assay shows that we can detect HN levels in SH-SY5Y cells. Hence for the
Supplement research we propose is to conduct screening for HN enhancers using the human neuroblastoma
SH-SY5Y cells that express and secrete HN [5]. The work we propose in the Supplement is directed toward
formatting of the available HN ELISA assay for HTS and screening of a subset of the UCLA compound library to
identify compounds that change HN levels in cells. Hits from the screening would be validated and then undergo
secondary testing to confirm HN enhancement in SH-SY5Y and iPSC-derived human neurons, as well as in
murine neuroblastoma N2a. Validated hits would also be assessed for increasing neuronal p-Akt. Thus, in the
supplement we propose an Expansion of Aim1 of the parent grant to include identification of HN enhancers
that along with our currently identified HN mimetics would undergo further testing and evaluation as outlined in
the parent grant. Hits from the screening would then undergo secondary testing to confirm HN enhancement in
SH-SY5Y and iPSC-derived human neurons, as well as in murine neuroblastoma N2a cells. Validated hits would
also be assessed using our p-Akt AlphaLISA to confirm biological activity in neurons. Validated HN enhancers
would undergo prioritization as part of Expansion of Aim3 of the parent grant by evaluation in in vitro ADME-T
assays. Prioritized analogs would undergo pharmacokinetic (PK) and pharmacodynamics (PD) studies to identify
brain permeable HN enhancers. Such an HN enhancers identified from the supplement grant would have the
potential to be developed as novel therapeutic candidates for Alzheimer's disease (AD), and could in the future
also be evaluated in other disorders such as diabetes and cardiovascular disease.
文摘(补充)
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)
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Varghese John其他文献
Varghese John的其他文献
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{{ 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:
$ 27.48万 - 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:
$ 27.48万 - 项目类别:
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
- 批准号:
10195566 - 财政年份:2021
- 资助金额:
$ 27.48万 - 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:
$ 27.48万 - 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:
$ 27.48万 - 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:
$ 27.48万 - 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:
$ 27.48万 - 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:
$ 27.48万 - 项目类别:
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