Accelerated Cerebrovascular Aging in a Fibrillin-1 Mutated Mouse Model

Fibrillin-1 突变小鼠模型加速脑血管老化

• 批准号: 10727231
• 负责人: Tala Curry-Koski
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727231
• 关键词: 3-Dimensional; Acceleration; Address; Age; Age Months; Aging; Aneurysm; Aorta; Arteries; Attention deficit hyperactivity disorder; Attenuated; Behavior; Binding; Biological; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain region; Breeding; C57BL/6 Mouse; Cerebral Aneurysm; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Connective Tissue Diseases; Data; Disease; Dissection; Elasticity; Elastin; Elastin Fiber; Endothelium; Extracellular Matrix; Extravasation; FBN1; Female; Frequencies; Functional disorder; Genes; Genetic; Glutamates; Goals; Headache; Heritability; Hippocampus; Hypertrophy; Immunohistochemistry; Impairment; Incidence; Individual; Induced Mutation; Inflammation; Inflammatory; Investigation; Kinetics; Knowledge; Life; Location; MMP2 gene; MMP9 gene; Marfan Syndrome; Matrix Metalloproteinases; Measures; Mediating; Mentors; Microelectrodes; Microglia; Migraine; Modeling; Molecular; Morphology; Mus; Muscle; Mutate; Mutation; Neurologic; Neurologic Deficit; Outcome; Pathway interactions; Patients; Peripheral; Plasma; Play; Prevention; Production; Proteins; Public Health; Publications; Quality of life; Randomized; Rattus; Regional Perfusion; Reporting; Research; Resources; Risk; Risk Factors; Role; Rupture; Severities; Sex Bias; Sex Differences; Signal Pathway; Signal Transduction; Signaling Molecule; Stroke; Structure; Structure of choroid plexus; Structure of posterior cerebral artery; TGFB1 gene; Testing; Transforming Growth Factor beta; Ultrasonography; Vascular Diseases; Wild Type Mouse; aged; aging population; arterial stiffness; autosome; biological sex; blood-brain barrier permeabilization; bone; cerebrovascular; cerebrovascular pathology; comparison control; cytokine; dementia risk; endothelial dysfunction; ethnic bias; experimental study; fluid percussion injury; glial activation; high risk; improved; in vivo; inflammatory marker; interest; male; middle cerebral artery; mild traumatic brain injury; mouse model; neurobehavioral; neuropathology; neurotransmission; new therapeutic target; normal aging; novel; patient population; personalized medicine; pre-clinical; preservation; prevent; scaffold; sex; therapeutic target; vascular cognitive impairment and dementia

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.

项目概要/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。 马凡氏综合征（MFS）是最常见的单基因常染色体显性遗传性结缔组织病， 其特征在于编码Fbn 1的基因突变，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支持，也为弹性蛋白纤维提供支架 细胞因子的作用是促进细胞成熟并结合细胞因子和防止有害的下游信号传导。MFS相关Fbn 1 突变导致危及生命的问题的风险增加，涉及血管壁的弱化 会导致扩张剥离和破裂Fbn 1基因突变对脑血管功能的影响 尽管MFS会导致神经功能缺损，包括头痛，偏头痛， 脑动脉瘤中风和注意力缺陷多动障碍细胞外基质（ECM）损伤， 血管壁变薄、变硬，血脑屏障（BBB）通透性增加，细胞因子水平升高 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 在衰老和MFS中的表现是由于增加的转化生长因子-β（TGF-β）信号传导而发生的。在 在小鼠中，Fbn 1突变在6月龄（6 M）时诱导血管功能障碍。这种易于使用的模型具有 在290多项研究中使用，其中只有两项研究涉及血管， 大脑中动脉（MCA）壁/管腔肥大增加， 脉络丛中MCA、BBB通透性、TGF-β细胞因子和MMP的产生。这些结果和 来自该实验室的数据表明，在该模型中， 正常衰老但速度加快这导致了Fbn 1突变加速的假设 脑血管功能和神经行为改变中与年龄相关的损害。为了测试这一点，Fbn 1 +/- 将评价6个月的C57 BL/6小鼠以及6个月（CTRL）和12个月（WT）的C57 BL/6小鼠的脑血管变化 目的：1）检测血浆中TGF-β信号分子的表达， 和Fbn 1 +/-小鼠模型中的海马。2)评价脑血管结构和功能 Fbn 1 +/-小鼠模型。3)在Fbn 1 +/-小鼠模型中检查神经病理学形态和功能。一 强大的指导团队支持这一提议，并提供专门知识和资源。本实验数据支持 Fbn 1突变在加速脑血管衰老和神经病理学中起着关键作用， 在神经损伤（如轻度创伤性脑损伤）后出现更严重结局的脆弱性风险。 影响：这是首次研究Fbn 1突变作为加速脑血管老化的贡献者 和功能障碍，其中TGF-β信号通路可以揭示 预防和保护MFS中血管功能障碍和神经病理学的增加，类似于 结缔组织疾病和人口老龄化。