Novel Knock in Mutation Rat Model for CARASIL
CARASIL 突变大鼠模型的新颖敲击
基本信息
- 批准号:10518554
- 负责人:
- 金额:$ 44.31万
- 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:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAlopeciaAlzheimer&aposs DiseaseAnimal ModelArterial DisorderBasal GangliaBrain PathologyBrain StemBrain hemorrhageCerebral Amyloid AngiopathyCerebral InfarctionCerebral small vessel diseaseCerebrumClinicalCognitiveDiabetes MellitusDiseaseElderlyExcisionExhibitsExtracellular MatrixFabry DiseaseFailureGait abnormalityGenesGoalsHigh temperature of physical objectHypertensionInheritedIschemic StrokeKnock-inLacunar InfarctionsLesionLeukoencephalopathyMagnetic Resonance ImagingModelingMolecularMotorMouse ProteinMusMutationPathogenesisPathologicPathologyPatientsPeptide HydrolasesProteinsRare DiseasesRattusResearch PersonnelSerine ProteaseSignal TransductionSmooth MuscleSmooth Muscle MyocytesSpondylosisStrokeStudy modelsSubcortical InfarctionsSubcortical LeukoencephalopathyTertiary Protein StructureTherapeuticTissuesWorkbrain sizecarboxypeptidase Ccerebral arteriopathycerebral microbleedsexperimental studyfallshuman diseaseimaging studyknockout genemouse modelmuscle degenerationmutantneuroimagingnovelpre-clinicalprotein complexvascular cognitive impairment and dementiawhite matterwhite matter changewhite matter damage
项目摘要
Cerebral small vessel diseases (CSVD) are a major cause of vascular cognitive impairment and dementia
(VCID) in the elderly, account for a significant number of ischemic and hemorrhagic strokes and are present in
Alzheimer’s disease and related disorders (ADRD). CSVDs broadly fall into two classes: 1) amyloidal CVSD
including sporadic and familial forms of cerebral amyloid angiopathy (CAA) and ADRD and 2) non-amyloidal
CSVD involving common conditions such as hypertension, diabetes, arteriolosclerosis and a number of rare
monogenic hereditary forms that includes cerebral autosomal recessive arteriopathy with subcortical infarcts and
leukoencephalopathy (CARASIL), which is a rare autosomal recessive, inherited non-hypertensive CSVD that
presents with early adult-onset VCID, gait disturbances, alopecia and spondylosis. Magnetic resonance imaging
(MRI) studies of CARASIL patients show pronounced white matter (WM) changes including multiple lacunar
infarcts, extensive WM lesions predominantly involving basal ganglia and brain stem and, in some cases,
subcortical cerebral microbleeds. The WM lesions appear to result from small vessel damage characterized by
extensive loss of cerebral arterial smooth muscle cells, loss of mural extracellular matrix and thickening and
fragmentation of the internal elastic lamina. Although monogenic forms of CSVD are rare they share many clinical
and neuropathological features with more common sporadic CSVDs including white matter damage, cerebral
infarcts, cerebral bleeds and VCID.
Previous studies have revealed that CARASIL results from specific mutations in the highly conserved high
temperature requirement serine proteinase A1 (htra1) gene that markedly reduce or abolish the serine proteinase
activity of Htra1 protein and believed to cause disruption of normal TGFb signaling that leads to smooth muscle
degeneration and other cerebral arteriopathies in CARASIL patients. Mechanistic studies of CARASIL are
hindered by the lack of effective animal models that faithfully recapitulate pathological features of human disease.
Accordingly, the overall aim of this exploratory proposal is to generate and characterize a novel rat
model of CARASIL by introducing a specific CARASIL mutation (R302Q) in the endogenous rat htra1
gene that will eliminate serine proteinase activity. To accomplish this overall goal, we propose the following
three sets of experiments: First, we will conduct molecular and pathological characterization of a novel mutant
‘knock in’ rat model for CARASIL. Second, we will determine the consequences of emerging CSVD pathology
on advanced cognitive and motor functions in the novel CARASIL rats. Lastly, we will perform neuroimaging
studies to determine the impact of emerging CSVD on brain pathology as defined by MRI in the novel CARASIL
rats. Successful completion of this work will provide a novel and unique animal model to the field of CSVD to
more fully understand how this condition contributes to cerebral arteriopathy, WM damage and VCID. Further, it
will provide a novel platform to investigate therapeutic strategies to target these pathologies in VCID and ADRD.
脑小血管病是血管性认知功能障碍和痴呆的主要原因
(VCID)在老年人中,占缺血性和出血性中风的显着数量,并存在于
阿尔茨海默病及相关疾病(ADRD)。CSVD大致分为两类:1)淀粉样CVSD
包括散发性和家族性形式的脑淀粉样血管病(CAA)和ADRD,和2)非淀粉样
CSVD涉及常见疾病,如高血压、糖尿病、小动脉硬化和一些罕见疾病。
单基因遗传形式,包括伴有皮质下梗死的常染色体隐性脑动脉病,
脑白质病(CARASIL)是一种罕见的常染色体隐性遗传性非高血压CSVD,
表现为早期成人发作的VCID、步态障碍、脱发和关节强硬。磁共振成像
(MRI)CARASIL患者的研究显示明显的白色物质(WM)改变,包括多个腔隙性病变,
梗死,主要涉及基底节和脑干的广泛WM病变,在某些情况下,
大脑皮层下微出血WM病变似乎是由小血管损伤引起的,
脑动脉平滑肌细胞大量丢失,壁细胞外基质丢失和增厚,
内弹性膜破裂。虽然单基因形式的CSVD是罕见的,但它们具有许多临床特征。
和神经病理学特征,包括白色物质损害、脑
梗塞脑出血和VCID
先前的研究表明,CARASIL是由高度保守的高表达基因中的特定突变引起的。
显著减少或消除丝氨酸蛋白酶的温度要求丝氨酸蛋白酶A1(htra1)基因
Htra1蛋白的活性,据信会破坏正常的TGF β信号传导,导致平滑肌
CARASIL患者中的变性和其他脑动脉病。对CARASIL的机制研究是
由于缺乏能如实再现人类疾病病理特征的有效动物模型而受到阻碍。
因此,该探索性提议的总体目标是产生和表征新的大鼠
通过在内源性大鼠htra1中引入特定CARASIL突变(R302Q)的CARASIL模型
消除丝氨酸蛋白酶活性的基因。为实现这一总体目标,我们提出以下建议
三组实验:首先,我们将对一种新的突变体进行分子和病理学表征
CARASIL的“敲入”大鼠模型。其次,我们将确定新出现的CSVD病理的后果,
对新型CARASIL大鼠的高级认知和运动功能的影响。最后,我们将进行神经成像
确定新发CSVD对新型CARASIL中MRI定义的脑病理学影响的研究
大鼠本工作的成功完成将为CSVD领域提供一种新颖独特的动物模型,
更充分地了解这种情况如何有助于脑动脉病,WM损害和VCID。此外,它
将提供一个新的平台,研究治疗策略,以针对这些病理VCID和ADRD。
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 }}
Helene D Benveniste其他文献
Helene D Benveniste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('Helene D Benveniste', 18)}}的其他基金
Chronic Alcohol, Dementia, and CNS Fluid Homeostasis
慢性酒精、痴呆和中枢神经系统液体稳态
- 批准号:
10467520 - 财政年份:2022
- 资助金额:
$ 44.31万 - 项目类别:
Chronic Alcohol, Dementia, and CNS Fluid Homeostasis
慢性酒精、痴呆和中枢神经系统液体稳态
- 批准号:
10706469 - 财政年份:2022
- 资助金额:
$ 44.31万 - 项目类别:
Lymphatics-Glymphatics in CNS Fluid Homeostasis
CNS 液体稳态中的淋巴管-类淋巴管
- 批准号:
10371201 - 财政年份:2021
- 资助金额:
$ 44.31万 - 项目类别:
Robust workflow software for MRI tracking of glymphatic-lymphatic coupling
用于 MRI 跟踪类淋巴耦合的强大工作流程软件
- 批准号:
10609195 - 财政年份:2021
- 资助金额:
$ 44.31万 - 项目类别:
Lymphatics-Glymphatics in CNS Fluid Homeostasis
CNS 液体稳态中的淋巴管-类淋巴管
- 批准号:
10212759 - 财政年份:2021
- 资助金额:
$ 44.31万 - 项目类别:
Lymphatics-Glymphatics in CNS Fluid Homeostasis
CNS 液体稳态中的淋巴管-类淋巴管
- 批准号:
10595682 - 财政年份:2021
- 资助金额:
$ 44.31万 - 项目类别:
Nitric oxide-mediated changes in glymphatic and CSF systems in aging and Alzheimer's disease
一氧化氮介导的类淋巴和脑脊液系统在衰老和阿尔茨海默病中的变化
- 批准号:
10177549 - 财政年份:2017
- 资助金额:
$ 44.31万 - 项目类别:
Characterizing the glymphatic peri-vascular connectome and its disruption in AD
AD 中类淋巴血管周围连接组的特征及其破坏
- 批准号:
9452462 - 财政年份:2017
- 资助金额:
$ 44.31万 - 项目类别:
Characterizing the glymphatic peri-vascular connectome and its disruption in AD
AD 中类淋巴血管周围连接组的特征及其破坏
- 批准号:
9193854 - 财政年份:2016
- 资助金额:
$ 44.31万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 44.31万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 44.31万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 44.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 44.31万 - 项目类别:
Studentship