Understanding the Origins of Amyloid Deposition in Cerebral Amyloid Angiopathy
了解脑淀粉样血管病中淀粉样蛋白沉积的起源
基本信息
- 批准号:9919003
- 负责人:
- 金额:$ 38.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-10-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAmyloidAmyloid FibrilsAmyloid beta-42Amyloid beta-ProteinAmyloid depositionBindingBiological MarkersBlood VesselsBrainCerebral Amyloid AngiopathyCerebrovascular systemChronicChronologyDementiaDepositionDevelopmentDiseaseEnvironmentFamilial Cerebral Amyloid AngiopathyFamilial diseaseFutureGangliosidesGoalsHemorrhageHumanIn VitroInflammationInvestigationIowaIschemiaKnowledgeLaboratoriesMembraneMutationNMR SpectroscopyNaturePathogenesisPathologicPatientsPeptidesPrevalenceProcessProductionProtein PrecursorsProteinsResearchSamplingSeedsSenile PlaquesSpectroscopy, Fourier Transform InfraredSporadic Cerebral Amyloid AngiopathyStructureSystemTransgenic MiceVariantVascular Cognitive Impairmentabeta accumulationamyloid formationamyloid pathologyamyloid structurebrain parenchymabrain tissuecerebrovascularcomorbiditydiagnostic biomarkerearly onseteffective therapyhuman diseasehypoperfusionmembrane modelmonomermouse modelmutantnovel therapeutic interventionpreferenceprotein aminoacid sequencepublic health relevancevascular cognitive impairment and dementia
项目摘要
DESCRIPTION (provided by applicant): Cerebrovascular accumulation of the amyloid ß-protein (Aß), a condition known as cerebral amyloid angiopathy (CAA), is an important driver of vascular cognitive impairment and dementia (VCID) and is a common comorbidity of patients with Alzheimer's disease (AD). CAA can promote VCID through a number of mechanisms including chronic inflammation, hypoperfusion and ischemia, loss of vessel wall integrity and hemorrhage. In addition to its prevalence in AD, several related familial CAA disorders result from specific mutations that reside within the Aß peptide sequence of the Aß precursor protein including the Dutch-type (E22Q) and Iowa-type (D23N) mutations. Despite the highly fibrillogenic nature of Dutch mutant and Iowa mutant Aß peptides, fibrillar Aß is restricted to te cerebral vasculature in these familial disorders. Recent evidence suggests the cerebral vascular amyloid is distinct from parenchymal plaque amyloid. However, there is a poor understanding as to why cerebral vascular amyloid forms and its unique structural features that promotes distinct pathological consequences leading to VCID. Thus, the focus of this proposal is to fill this critica void in knowledge. Accordingly, the overall hypothesis of this proposal is that fibrillar amyloid i cerebral blood vessels possesses distinct structural features compared to parenchymal fibrillar amyloid and unique anti-parallel structures, enhanced by CAA mutations, drives the cerebral vascular specific deposition of amyloid in brain. To address this hypothesis we propose three specific aims. First, we will determine the structure, assembly and membrane interactions of wild-type and the Dutch and Iowa CAA mutants of Aß in solution and model membrane systems that drive their compartmental deposition. Second, we will determine how familial CAA variants of Aß chronologically influence the structural features and assembly of wild-type Aß in the brains of transgenic mice. Third, we will isolate parenchymal plaque amyloid and cerebral vascular amyloid from post mortem brain tissue of AD cases, sporadic CAA cases and familial CAA cases and investigate their ability to promote assembly of wild-type and CAA mutant Aß peptides. These important studies will reveal the distinct structural signatures of cerebral vascular and parenchymal plaque amyloid deposits in human disease. Presently, there are no reliable biomarkers or effective therapies specifically for CAA and VCID. These deficiencies are complicated by our lack of understanding of the unique structural attributes of cerebral vascular amyloid and its early-stage oligomeric precursors, and their distinctive features and processes compared to parenchymal plaque amyloid. The present proposal will seek to fill this critical void in our knowledge and will advance our understanding of the pathogenesis of CAA and provide the basis for the future development of novel therapeutic interventions and diagnostic markers for CAA and VCID.
描述(由申请方提供):淀粉样β-蛋白(A β)的脑血管蓄积,一种称为脑淀粉样血管病(CAA)的疾病,是血管性认知障碍和痴呆(VCID)的重要驱动因素,也是阿尔茨海默病(AD)患者的常见合并症。CAA可通过多种机制促进VCID,包括慢性炎症、低灌注和缺血、血管壁完整性丧失和出血。除了其在AD中的患病率之外,几种相关的家族性CAA病症是由存在于Abluc前体蛋白的Abluc肽序列内的特定突变引起的,包括Dutch型(E22 Q)和Iowa型(D23 N)突变。尽管Dutch突变型和爱荷华州突变型ApoA肽具有高度纤维形成的性质,但在这些家族性疾病中,纤维状ApoA仅限于脑血管系统。最近的证据表明脑血管淀粉样蛋白不同于脑实质斑块淀粉样蛋白。然而,对于脑血管淀粉样蛋白形成的原因以及其独特的结构特征促进导致VCID的独特病理后果的理解很少。因此,这个建议的重点是填补知识的这一关键空白。因此,该提议的总体假设是,与实质纤维状淀粉样蛋白相比,脑血管中的纤维状淀粉样蛋白具有独特的结构特征,并且通过CAA突变增强的独特的反平行结构驱动淀粉样蛋白在脑中的脑血管特异性沉积。 为了解决这一假设,我们提出了三个具体目标。首先,我们将确定野生型和荷兰和爱荷华州CAA的突变体的结构,装配和膜相互作用的ARAMINE在溶液和模型膜系统,驱动其房室沉积。第二,我们将确定如何家族性CAA变异的ARAPINE按时间顺序影响的结构特征和组装的野生型ARAPINE在转基因小鼠的大脑。第三,我们将从AD病例、散发性CAA病例和家族性CAA病例的死后脑组织中分离出实质斑块淀粉样蛋白和脑血管淀粉样蛋白,并研究它们促进野生型和CAA突变型A β肽组装的能力。这些重要的研究将揭示人类疾病中脑血管和脑实质斑块淀粉样蛋白沉积的独特结构特征。 目前,还没有可靠的生物标志物或有效的治疗方法专门用于CAA和VCID。由于我们对脑血管淀粉样蛋白及其早期寡聚前体的独特结构属性及其与实质斑块淀粉样蛋白相比的独特特征和过程缺乏了解,这些缺陷变得复杂。目前的建议将寻求填补这一关键空白,在我们的知识,并将促进我们的CAA的发病机制的理解,并提供新的治疗干预和CAA和VCID的诊断标志物的未来发展的基础。
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)
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STEVEN Owen SMITH其他文献
STEVEN Owen SMITH的其他文献
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{{ truncateString('STEVEN Owen SMITH', 18)}}的其他基金
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
9672144 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
10405031 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
9789805 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Structural Identification and Functional Consequences of Different Amyloid Strains in Alzheimer's Disease
阿尔茨海默病中不同淀粉样蛋白菌株的结构鉴定和功能后果
- 批准号:
10176329 - 财政年份:2018
- 资助金额:
$ 38.38万 - 项目类别:
Understanding the Origins of Amyloid Deposition in Cerebral Amyloid Angiopathy
了解脑淀粉样血管病中淀粉样蛋白沉积的起源
- 批准号:
9251922 - 财政年份:2016
- 资助金额:
$ 38.38万 - 项目类别:
Mechanism of inhibition of APP processing and amyloid formation
APP 加工和淀粉样蛋白形成的抑制机制
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8332308 - 财政年份:2006
- 资助金额:
$ 38.38万 - 项目类别:
Structure-inhibition of amyloid oligomers and fibrils
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7866473 - 财政年份:2006
- 资助金额:
$ 38.38万 - 项目类别:
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