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.

项目摘要/摘要： 与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疾病， 其特征是编码 fibrillin-1 (Fbn1) 的基因发生突变，Fbn1 没有性别或种族偏见。 蛋白质为肌肉、骨骼和血管提供结构支撑，并为弹性蛋白纤维提供支架 成熟并结合细胞因子并防止 MFS 相关的 Fbn1 下游信号传导。 突变导致与血管壁减弱有关的危及生命的问题的风险增加 Fbn1 突变对脑血管功能的影响可能导致扩张、夹层和破裂。 尽管 MFS 会导致神经功能缺陷，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， 血管壁变弱、变硬、血脑屏障（BBB）通透性和细胞因子加剧 产生是与脑血管衰老相关的标志性改变，并且在 MFS 中普遍存在。 衰老和 MFS 的表现是由于转化生长因子-β (TGF-β) 信号传导增加而发生的。 在小鼠中，Fbn1 突变会在 6 个月 (6M) 龄时诱发血管功能障碍。 已被用于 290 多项研究，其中只有两项涉及脑血管系统，表明 大脑中动脉 (MCA) 壁/管腔肥大、基质金属蛋白酶 (MMP) 增加 MCA、BBB 通透性以及脉络丛中 TGF-β 细胞因子和 MMP 的产生。 该实验室的数据表明，该模型中的脑血管老化速度加快，与 正常衰老，但速度加快，这导致了 Fbn1 突变加速的假设。 与衰老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+/-。 将评估 6M 小鼠以及 6（CTRL）和 12M（WT）C57BL/6 小鼠的脑血管改变 通过这些目标进行神经病理学：1) 测量血浆中 TGF-β 信号分子的表达 和 Fbn1+/- 小鼠模型中的海马 2) 评估脑血管结构和功能。 Fbn1+/- 小鼠模型。3) 检查 Fbn1+/- 小鼠模型的神经病理形态和功能。 强大的指导团队支持该提案并提供来自该实验室的专业知识和资源。 Fbn1 突变在加速脑血管老化和神经病理学方面发挥着关键作用， 神经损伤（例如轻度创伤性脑损伤）后容易出现更严重后果的风险。 影响：这是对 Fbn1 突变导致脑血管加速老化的首次研究 和功能障碍，TGF-β信号通路可能揭示机制和治疗靶点 预防和保护 MFS 中增加的血管功能障碍和神经病理学，类似 结缔组织疾病和人口老龄化。