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

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

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Helene D Benveniste其他文献

Helene D Benveniste的其他文献

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{{ 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:
Research Supplement for Kennelia Mellanson
肯尼莉亚·梅兰森的研究增刊
  • 批准号:
    10382622
  • 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:

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