Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome
唐氏综合症中蛋白质稳态失调以及阿尔茨海默病样神经变性和痴呆的发展
基本信息
- 批准号:10595310
- 负责人:
- 金额:$ 52.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-01 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAmyloidAnimal ModelAutopsyBehaviorBiochemicalBirthBrainBrain PathologyBrain regionCatabolismCell DeathCell physiologyCellsCessation of lifeChromosome 21ChromosomesCongenital DisordersDataDefectDementiaDepositionDevelopmentDown SyndromeEventFRAP1 geneFunctional disorderGene ProteinsHealthHuman ChromosomesHyperactivityIncidenceIndividualKnowledgeLinkLiteratureModelingNerve DegenerationNeurofibrillary TanglesNeuronsOrganPathogenesisPathologicPathologyPathway interactionsPatientsPeptidesPhenotypePhysiologicalPlayProtein BiosynthesisProtein PrecursorsProteinsPublishingResearchRoleSecondary toSenile PlaquesSignal PathwaySignal TransductionSynapsesSyndromeSystemTrisomyTuberous SclerosisUnited Statesbehavioral impairmentbrain tissuegene productin vivo Modelmouse Ts65Dnmouse modelneuron lossneuropathologynovelnovel therapeuticsprogramsprotein degradationproteostasissecretasetau Proteinstau aggregationtherapeutic targettooltraffickingvirtual
项目摘要
Down syndrome (DS) is a congenital condition resulting from partial or complete triplication of
human chromosome 21. Virtually all the subjects with DS develop widespread neuropathology
including amyloid- neuritic plaques, synaptic dysfunction and neurodegeneration, reminiscent of
Alzheimer's disease. While the extra copy of amyloid- precursor protein (APP) on chromosome
21 is thought to play a major role in the development of this type of pathologic phenotype in DS,
the underlying mechanisms responsible for these changes and their contribution to
neurodegeneration are still elusive. Compelling evidence supports the hypothesis that
physiological cellular proteostasis is of critical importance for neuronal health and that the
mammalian target of rapamycin (mTOR) is a master regulator of this vital cellular function.
However, while we know that the system is altered in DS we do not know whether it plays a
functional role in the pathogenesis of DS and the onset of neuropathology. In our preliminary data
we found that compared with healthy matched controls mTOR is hyperactive in selected brain
regions of DS patients. Importantly, we observed that in the same subjects the dysfunction directly
correlates with the pathology. Moreover, we show that mTOR is altered in the brain of a well-
established mouse model of DS, the Ts65Dn mice, at an early stage of the phenotype, and
associates with biochemical evidence of cell loss, suggesting a link between mTOR,
neuropathology and neurodegeneration in DS subjects. Taking into consideration the scientific
rigor of the previously published literature together with our recent findings we now propose a
novel working hypothesis: alteration of mTOR signaling pathway is responsible for the onset of
the neuropathologic DS phenotype and represents a novel and viable therapeutic target against
it in DS subjects. In this proposal, we will assess the temporal relationship between dysregulation
of mTOR in the brain of DS patients and the development of the neuropathology. We will then
focus on investigating early events responsible for this dysregulation in the same DS subjects.
Next, to prove its direct role in the pathogenesis of the syndrome, we will study the effect that
modulation of mTOR activity and expression levels has on behavior impairments and
neuropathology using in vivo models of DS. The results of our proposed studies will elucidate
early changes and the functional consequences of altered proteostasis secondary to dysregulated
mTOR in the development of the neuropathologic phenotype in individuals with DS. Importantly,
our findings have the potential to identify new therapeutic opportunities for delaying its onset and
/or halting its progression.
唐氏综合征(DS)是一种先天性疾病,由部分或完全三重先天性发育不良引起。
人类21号染色体事实上,所有患有DS的受试者都出现了广泛的神经病理学
包括淀粉样蛋白-神经炎斑块、突触功能障碍和神经退行性变,让人想起
老年痴呆症而染色体上的淀粉样前体蛋白(APP)
21被认为在DS中这种类型的病理表型的发展中起主要作用,
造成这些变化的基本机制及其对
神经退行性变仍然是难以捉摸的。令人信服的证据支持这样的假设,
生理性细胞蛋白质稳态对神经元健康至关重要,
哺乳动物雷帕霉素靶蛋白(mTOR)是这种重要细胞功能的主要调节剂。
然而,虽然我们知道系统在DS中发生了变化,但我们不知道它是否起作用。
在DS发病机制和神经病理学发病中的功能作用。在我们的初步数据中
我们发现,与健康对照组相比,mTOR在选定的大脑中过度活跃,
DS患者的区域。重要的是,我们观察到,在相同的受试者中,
与病理学有关此外,我们表明,mTOR在一个良好的大脑中发生了改变-
在表型的早期阶段建立DS的小鼠模型,Ts 65 Dn小鼠,和
与细胞损失的生化证据有关,表明mTOR,
神经病理学和神经变性。考虑到科学
先前发表的文献的严谨性以及我们最近的发现,我们现在提出一个
一种新的工作假设:mTOR信号通路的改变是导致
神经病理性DS表型,代表了一种新的可行的治疗靶点,
在DS主题中。在这个建议中,我们将评估调节异常与
mTOR在DS患者脑中的表达及神经病理学的发展。然后我们将
重点研究在相同DS受试者中导致这种失调的早期事件。
接下来,为了证明其在综合征发病机制中的直接作用,我们将研究
mTOR活性和表达水平的调节对行为障碍有影响,
使用DS的体内模型的神经病理学。我们建议的研究结果将阐明
继发于失调的蛋白质稳态改变的早期变化和功能后果
mTOR在DS患者神经病理表型发展中的作用重要的是,
我们的研究结果有可能发现新的治疗机会,以延迟其发病,
或阻止其进展。
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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DOMENICO PRATICO其他文献
DOMENICO PRATICO的其他文献
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{{ truncateString('DOMENICO PRATICO', 18)}}的其他基金
Alzheimer's tauopathy phenotype and the microRNA22-3p: implication for pathogenesis
阿尔茨海默病 tau 蛋白病表型和 microRNA22-3p:对发病机制的影响
- 批准号:
10282121 - 财政年份:2021
- 资助金额:
$ 52.33万 - 项目类别:
Alzheimer's tauopathy phenotype and the microRNA22-3p: implication for pathogenesis
阿尔茨海默病 tau 蛋白病表型和 microRNA22-3p:对发病机制的影响
- 批准号:
10662386 - 财政年份:2021
- 资助金额:
$ 52.33万 - 项目类别:
Dissecting the role of 5LO in neurodegeneration associated with homocysteine
剖析 5LO 在与同型半胱氨酸相关的神经变性中的作用
- 批准号:
9106037 - 财政年份:2016
- 资助金额:
$ 52.33万 - 项目类别:
5Lipoxygenase-mediated vasculopathy in HHcy
5 HHcy 中脂氧合酶介导的血管病变
- 批准号:
9043941 - 财政年份:2013
- 资助金额:
$ 52.33万 - 项目类别:
5Lipoxygenase-mediated vasculopathy in HHcy
5 HHcy 中脂氧合酶介导的血管病变
- 批准号:
8667496 - 财政年份:2013
- 资助金额:
$ 52.33万 - 项目类别:
5Lipoxygenase-mediated vasculopathy in HHcy
5 HHcy 中脂氧合酶介导的血管病变
- 批准号:
8438046 - 财政年份:2013
- 资助金额:
$ 52.33万 - 项目类别:
The functional role of FLAP in Alzheimer's Disease
FLAP 在阿尔茨海默病中的功能作用
- 批准号:
8114511 - 财政年份:2011
- 资助金额:
$ 52.33万 - 项目类别:
The functional role of FLAP in Alzheimer's Disease
FLAP 在阿尔茨海默病中的功能作用
- 批准号:
8309154 - 财政年份:2011
- 资助金额:
$ 52.33万 - 项目类别:














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