Accelerated Cerebrovascular Aging in a Fibrillin-1 Mutated Mouse Model

项目摘要/摘要： 衰老相关的血管和脑血管功能障碍在许多结缔组织疾病中普遍存在。 马凡综合征(MFS)是最常见的单基因常染色体显性结缔组织病， 以纤维蛋白-1(Fbn1)编码基因突变为特征，没有性别或种族偏见。FBN1 蛋白质为肌肉、骨骼和血管提供结构性支持，也为弹性蛋白纤维提供支架。 成熟，结合细胞因子，防止有害的下游信号。与MFS关联的Fbn1 突变导致发生危及生命的问题的风险增加，这些问题涉及血管壁的削弱 这可能会导致扩张、夹层和破裂。Fbn1基因突变对脑血管功能的影响 尽管MFS会导致包括头痛、偏头痛在内的神经功能障碍，但几乎没有得到解决， 脑动脉瘤、中风和注意缺陷多动障碍。细胞外基质(ECM)损伤， 血管壁变弱和变硬，血脑屏障(BBB)通透性和细胞因子加剧 产生是与脑血管老化相关的标志性改变，在MFS中普遍存在。这些 衰老和多发性硬化症的表现是由于转化生长因子-β(β)信号的增加。在……里面 小鼠，Fbn1突变导致6个月龄(6个月)的血管功能障碍。这款易于使用的型号具有 已在290多项研究中使用，其中只有两项涉及脑血管系统，展示了 大脑中动脉(MCA)管壁/管腔肥厚、基质金属蛋白酶(MMPs)表达增加 脉络丛的大脑中动脉、血脑屏障通透性、转化生长因子-β细胞因子和基质金属蛋白酶的产生。这些结果和 来自该实验室的数据表明，在这种模型中，脑血管老化的增加与 正常衰老，但速度加快。这导致了一种假设，即Fbn1突变加速 与年龄相关的脑血管功能和神经行为改变的损害。为了测试这一点，Fbn1+/- 6个月龄的小鼠，以及6个月龄(CTRL)和12个月龄(WT)的C57BL/6小鼠将被评估脑血管的变化 1)检测转化生长因子-β信号分子在血浆中的表达 以及Fbn1+/-小鼠模型中的海马体。2)评价老年人脑血管结构和功能 Fbn1+/-小鼠模型。3)检测Fbn1+/-小鼠模型的神经病理形态和功能。一个 强大的指导团队支持这一提议，并提供专业知识和资源。来自此实验室的数据支持 Fbn1突变在加速的脑血管老化和增加的神经病理中起关键作用 在神经侮辱后，如轻度创伤性脑损伤，易发生更严重后果的风险。 影响：这是第一次研究Fbn1突变是加速脑血管老化的因素 和功能障碍，其中转化生长因子-β信号通路可能揭示机制和治疗靶点 预防和保护MFS中血管功能障碍和神经病理的增加，类似 结缔组织疾病和人口老龄化。

Project Summary/Abstract: Aging-associated vascular and cerebrovascular dysfunction is prevalent in many connective tissue disorders. Marfan syndrome (MFS) is the most common monogenetic autosomal dominant disorder of connective tissue, characterized by mutations in the gene encoding for fibrillin-1 (Fbn1), with no gender or ethnic bias. Fbn1 protein provides structural support for muscles, bones, and blood vessels as well as a scaffold for elastin fiber maturation and to bind cytokines and prevent deleterious downstream signaling. MFS-associated Fbn1 mutation results in an increased risk of life-threatening problems involved in weakening of blood vessel walls that can lead to dilation, dissection, and rupture. The role of Fbn1 mutation on cerebrovascular function has barely begun to be addressed though MFS causes neurological deficits including headaches, migraines, cerebral aneurysms, stroke, and attention deficit hyperactivity disorder. Extracellular matrix (ECM) impairment, vascular wall weakening, and stiffening, blood brain barrier (BBB) permeability, and exacerbated cytokine production are hallmark alterations associated with cerebrovascular aging and are prevalent in MFS. These manifestations in aging and MFS occur due to increased transforming growth factor-beta (TGF-β) signaling. In mice, Fbn1 mutation induces vascular dysfunction by 6-month (6M) of age. This readily accessible model has been used in more than 290 studies, where only two have addressed the cerebrovasculature, demonstrating increased middle cerebral artery (MCA) wall/lumen hypertrophy, matrix metalloproteinases (MMPs) in the MCA, BBB permeability, and TGF-β cytokine and MMP production in the choroid plexus. These results and data from this lab suggest that increased cerebrovascular aging is occurring in this model similar to that of normal aging, but with an accelerated pace. This has led to the hypothesis that Fbn1 mutation accelerates aging-associated compromise in cerebrovascular function and neurobehavioral alterations. To test this, Fbn1+/- mice at 6M, and C57BL/6 mice at 6 (CTRL) and 12M (WT) will be evaluated for cerebrovascular alterations and neuropathology through these Aims: 1) measure the expression of TGF-β signaling molecules in plasma and the hippocampus in an Fbn1+/- mouse model. 2) evaluate cerebrovascular structure and function in an Fbn1+/- mouse model. 3) examine neuropathological morphology and function in an Fbn1+/- mouse model. A strong mentoring team supports this proposal and provides expertise and resources. Data from this lab support that Fbn1 mutation plays a critical role in accelerated cerebrovascular aging and neuropathology that increases the risk of vulnerability for more severe outcomes after neurological insult such as mild traumatic brain injury. Impact: This is the first investigation of Fbn1 mutation as a contributor to accelerated cerebrovascular aging and dysfunction, where the TGF-β signaling pathway may reveal mechanisms and therapeutic targets for prevention and protection against increasing vascular dysfunction and neuropathology in MFS, similar connective tissue disorders, and the aging population.