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.
摘要(补充)
Humanin(HN)是一种由24个氨基酸组成的脑源性肽,来自于死后散发的
AD患者脑组织[1]是一种神经保护肽,可以保护神经元免受Aβ相关和NMDA-
毒性[2]。据报道,内源性HN血浆水平随年龄增长而降低[3],
HN水平的降低与衰老过程中的认知能力下降有关。SNP(rs 2854128)的鉴定
使用来自大样本老年人的线粒体基因组HN编码区的线粒体GWAS,
成年人进一步支持HN及其循环水平的作用,加速认知能力下降[4]。的
高通量筛选(HTS)可格式化测定的可用性,允许筛选以鉴定小分子
能够增强AD模型中HN的表达及其水平。在父母补助金中,我们完成了对
小分子作为humanin(HN)模拟物,并已确定有效的命中,增加了p-
神经元细胞中的gp 130和p-Akt水平。对这些模拟物的进一步模拟、测试和评估正在进行中
遵循拨款中列出的路径。评估HN肽本身水平的新测定法的可用性,
在体外和组织中的研究也提供了鉴定提高HN水平的小分子的机会。我们
使用该测定法的初步数据显示我们可以检测SH-SY 5 Y细胞中的HN水平。因此对于
补充研究,我们建议进行筛选HN增强剂使用人类神经母细胞瘤
表达和分泌HN的SH-SY 5 Y细胞[5]。我们在补编中建议的工作是针对
对HTS的可用HN ELISA测定进行格式化,并筛选UCLA化合物文库的子集,
鉴定改变细胞中HN水平的化合物。筛选中的命中将被验证,
二次测试以确认SH-SY 5 Y和iPSC衍生的人神经元中的HN增强,以及
小鼠神经母细胞瘤N2 a。还将针对增加的神经元p-Akt评估验证的命中。因此在
补充,我们建议扩大父母补助金的目标1,以包括HN增强剂的鉴定
沿着我们目前鉴定的HN模拟物将进行进一步的测试和评估,如
家长补助金然后,筛选的命中将进行二次测试,以确认HN增强,
SH-SY 5 Y和iPSC衍生的人神经元,以及鼠神经母细胞瘤N2 a细胞中。经验证的命中率将
还可以使用我们的p-Akt AlphaLISA进行评估,以确认神经元中的生物活性。经验证的HN增强剂
将通过体外ADME-T评估,作为母基金Aim 3扩展的一部分进行优先排序
测定。优先的类似物将进行药代动力学(PK)和药效学(PD)研究,以鉴定
脑渗透性HN增强剂。从补充补助金中鉴定的这种HN增强剂将具有
有可能被开发为阿尔茨海默病(AD)的新的治疗候选人,并可能在未来
也可以在其他疾病如糖尿病和心血管疾病中进行评估。
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:
$ 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:
相似海外基金
Proton-secreting epithelial cells as key modulators of epididymal mucosal immunity - Administrative Supplement
质子分泌上皮细胞作为附睾粘膜免疫的关键调节剂 - 行政补充
- 批准号:
10833895 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
A Longitudinal Qualitative Study of Fentanyl-Stimulant Polysubstance Use Among People Experiencing Homelessness (Administrative supplement)
无家可归者使用芬太尼兴奋剂多物质的纵向定性研究(行政补充)
- 批准号:
10841820 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
StrokeNet Administrative Supplement for the Funding Extension
StrokeNet 资助延期行政补充文件
- 批准号:
10850135 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
2023 NINDS Landis Mentorship Award - Administrative Supplement to NS121106 Control of Axon Initial Segment in Epilepsy
2023 年 NINDS 兰迪斯指导奖 - NS121106 癫痫轴突初始段控制的行政补充
- 批准号:
10896844 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
Biomarkers of Disease in Alcoholic Hepatitis Administrative Supplement
酒精性肝炎行政补充剂中疾病的生物标志物
- 批准号:
10840220 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
Administrative Supplement: Life-Space and Activity Digital Markers for Detection of Cognitive Decline in Community-Dwelling Older Adults: The RAMS Study
行政补充:用于检测社区老年人认知衰退的生活空间和活动数字标记:RAMS 研究
- 批准号:
10844667 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
Administrative Supplement: Improving Inference of Genetic Architecture and Selection with African Genomes
行政补充:利用非洲基因组改进遗传结构的推断和选择
- 批准号:
10891050 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
Power-Up Study Administrative Supplement to Promote Diversity
促进多元化的 Power-Up 研究行政补充
- 批准号:
10711717 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
Administrative Supplement for Peer-Delivered and Technology-Assisted Integrated Illness Management and Recovery
同行交付和技术辅助的综合疾病管理和康复的行政补充
- 批准号:
10811292 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别:
Administrative Supplement: Genome Resources for Model Amphibians
行政补充:模型两栖动物基因组资源
- 批准号:
10806365 - 财政年份:2023
- 资助金额:
$ 27.48万 - 项目类别: