Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
基本信息
- 批准号:8741927
- 负责人:
- 金额:$ 32.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-30 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAdverse effectsAgeAge-associated memory impairmentAlzheimer&aposs DiseaseAmyloid beta-Protein PrecursorAmyloid depositionBehaviorBehavioralBiological ProcessBody SizeBody WeightBrainBreedingChromosomes, Human, Pair 21Cleaved cellClinical TrialsCognitive deficitsDeath RateDefectDementiaDevelopmentDown SyndromeDoxycyclineElderlyElementsEnzymesEpilepsyFunctional disorderGeneral PopulationGenerationsGenesGrowthHumanIncidenceIndividualKnockout MiceKnowledgeLeadLearningMediatingMembraneMemoryMemory impairmentModelingMolecularMusNeonatalNeuregulin 1Neurofibrillary TanglesNeurologicPathologyPatientsPhase II Clinical TrialsPhenotypePlasmaProductionProtein FragmentReportingRetinalRoleScheduleSchizophreniaSeizuresSenile PlaquesSodium ChannelStagingSurvival RateSynaptic TransmissionSystemTechnologyTestingTetanus Helper PeptideTetracycline ControlTherapeuticTimeTissuesTransgenic MiceVaccinesWild Type MouseWorkamyloid peptideaxonal guidancebasebeta-site APP cleaving enzyme 1cognitive functiondrug discoveryextracellularfunctional outcomeshuman studyimprovedinhibitor/antagonistmouse Ts65Dnmouse modelmyelinationoverexpressionpeptide Apostnatalpreventpublic health relevancerecombinaseresearch studysecretasesmall moleculesynaptic functiontau Proteinstherapeutic targetvoltage
项目摘要
DESCRIPTION (provided by applicant): Abnormal accumulation of amyloid-¿ peptide (A¿), which is generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and ?-secretase, is widely regarded as having a causal role in the development of Alzheimer's disease (AD). Individuals with Down syndrome (DS), due to an extra copy of chromosome 21 in which APP is located at 21q21, develop age-related cognitive decline and AD dementia by 30-40 years earlier than in the general population, and their brains invariantly develop amyloid plaques. Since cleavage of APP by BACE1 initiates the production of A¿, inhibition of BACE1 activity should decrease the formation of A¿ and is therefore a therapeutic target for AD. For the safe use of BACE1 inhibitors in humans, it is very important to fully understand the biological functions of BACE1 in the adult. Notably, neonatal BACE1-null mice have reduced body sizes and survival rates when compared to their age-matched wild-type littermates. However, the death rate is significantly decreased if BACE1-null mice can survive beyond postnatal day 10 and the differences in body weight become much smaller between BACE1-null and wild-type mice over time. In the adult, BACE1-null mice are fertile but do develop multiple mild to moderate phenotypes such as increases in the incidence of epileptic seizures, schizophrenia-like behaviors, retinal pathology, deficits in activity-dependent CA3 synaptic transmission, defects in axonal guidance and impaired myelination in BACE1-null mice. One potential explanation for these phenotypes in BACE1-null mice is the carryover effect from early developmental defects. To determine whether BACE1 is required for normal functions in adult mice, we have generated conditional BACE1 knockout mice and will delete BACE1 in the adult mouse. This new mouse model will allow us to answer questions such as whether inhibition of BACE1 activity in adult is safe and whether BACE1 inhibition at late ages will still e effective in removing preexisting amyloid plaques. This model will also be practical to answer the question of whether BACE1 inhibition in the adult will ameliorate tau pathology. Our central hypothesis in this proposal is that controlled inhibition of BACE1 activity will have optimal effecs on reducing or reversing AD pathologies. By testing our hypothesis, we will perform experiments in three specific aims. Aim 1: To characterize BACE1 conditional KO mice and to determine whether induced BACE1 deficiency will lead to phenotypic changes similar to those observed in BACE1-null mice. Aim 2: To determine whether induced BACE1 deficiency can reverse pre-formed amyloid plaques in AD transgenic mouse brains. Aim 3: to examine whether BACE1 inhibition will impact cognitive function in the Ts65Dn Down syndrome mouse model. The knowledge gained from this study will allow us to answer many unmet questions such as whether a significant reduction of BACE1 in the adult would have beneficial effects for reducing or eliminating AD and DS pathologies.
描述(由申请人提供):淀粉样肽(A¿)的异常积累,由淀粉样前体蛋白(APP)通过BACE1和β-分泌酶的两次连续蛋白水解裂解产生,被广泛认为在阿尔茨海默氏病(AD)的发展中具有因果作用。患有唐氏综合症(DS)的人,由于 APP 位于 21q21 的 21 号染色体有一个额外的拷贝,因此比普通人群早 30-40 年出现与年龄相关的认知能力下降和 AD 痴呆,并且他们的大脑总是会形成淀粉样斑块。由于 BACE1 裂解 APP 会引发 A¿ 的产生,因此抑制 BACE1 活性应该会减少 A¿ 的形成,因此是 AD 的治疗靶点。为了在人体中安全使用BACE1抑制剂,充分了解BACE1在成人中的生物学功能非常重要。值得注意的是,与年龄匹配的野生型同窝小鼠相比,新生 BACE1 缺失小鼠的体型和存活率均降低。然而,如果 BACE1 缺失小鼠能够存活超过出生后第 10 天,则死亡率会显着降低,并且随着时间的推移,BACE1 缺失和野生型小鼠之间的体重差异会变得更小。在成年中,BACE1缺失小鼠具有生育能力,但确实会出现多种轻度至中度表型,例如BACE1缺失小鼠癫痫发作的发生率增加、精神分裂症样行为、视网膜病理、活动依赖性CA3突触传递缺陷、轴突引导缺陷和髓鞘形成受损。 BACE1 缺失小鼠中这些表型的一种可能解释是早期发育缺陷的遗留效应。为了确定成年小鼠的正常功能是否需要 BACE1,我们生成了条件性 BACE1 敲除小鼠,并将删除成年小鼠中的 BACE1。这种新的小鼠模型将使我们能够回答诸如抑制成人 BACE1 活性是否安全以及晚年抑制 BACE1 是否仍能有效去除先前存在的淀粉样斑块等问题。该模型还可以实用地回答成人中 BACE1 抑制是否会改善 tau 病理学的问题。我们在该提案中的中心假设是,控制 BACE1 活性的抑制将对减少或逆转 AD 病理产生最佳效果。通过检验我们的假设,我们将针对三个特定目标进行实验。目标 1:表征 BACE1 条件性 KO 小鼠,并确定诱导的 BACE1 缺陷是否会导致与 BACE1 缺失小鼠中观察到的类似的表型变化。目标 2:确定诱导的 BACE1 缺陷是否可以逆转 AD 转基因小鼠大脑中预先形成的淀粉样斑块。目标 3:检查 BACE1 抑制是否会影响 Ts65Dn 唐氏综合症小鼠模型的认知功能。从这项研究中获得的知识将使我们能够回答许多未解决的问题,例如成人中 BACE1 的显着减少是否会对减少或消除 AD 和 DS 病理产生有益的影响。
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 }}
RIQIANG YAN其他文献
RIQIANG YAN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('RIQIANG YAN', 18)}}的其他基金
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
- 批准号:
10594845 - 财政年份:2022
- 资助金额:
$ 32.49万 - 项目类别:
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
- 批准号:
9691661 - 财政年份:2018
- 资助金额:
$ 32.49万 - 项目类别:
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
- 批准号:
9456462 - 财政年份:2017
- 资助金额:
$ 32.49万 - 项目类别:
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
- 批准号:
10709060 - 财政年份:2017
- 资助金额:
$ 32.49万 - 项目类别:
The secreted form of Neuregulin-1 in schizophrenia
精神分裂症中 Neuregulin-1 的分泌形式
- 批准号:
8925147 - 财政年份:2014
- 资助金额:
$ 32.49万 - 项目类别:
The secreted form of Neuregulin-1 in schizophrenia
精神分裂症中 Neuregulin-1 的分泌形式
- 批准号:
8825231 - 财政年份:2014
- 资助金额:
$ 32.49万 - 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
- 批准号:
8878977 - 财政年份:2013
- 资助金额:
$ 32.49万 - 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
- 批准号:
9304940 - 财政年份:2013
- 资助金额:
$ 32.49万 - 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
- 批准号:
9111767 - 财政年份:2013
- 资助金额:
$ 32.49万 - 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
- 批准号:
8641971 - 财政年份:2013
- 资助金额:
$ 32.49万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 32.49万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 32.49万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 32.49万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 32.49万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 32.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 32.49万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 32.49万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 32.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 32.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 32.49万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




