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

基本信息

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
项目类别：
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

项目摘要

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：在许多连接的组织疾病中，与老化相关的血管和脑血管功能障碍普遍存在。 Marfan综合征（MFS）是结缔组织最常见的单基因常染色体显性疾病，以原纤维蛋白1（FBN1）的基因编码中的突变为特征，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支持，以及弹性蛋白纤维的支架成熟并结合细胞因子并防止有害的下游信号传导。 MFS相关的FBN1 突变导致降低血管壁的威胁生命问题的风险增加这可能导致字典，解剖和破裂。 FBN1突变对脑血管功能的作用具有尽管MFS引起神经系统定义，包括标题，偏头痛，脑动脉瘤，中风和注意力不足多动障碍。细胞外基质（ECM）损伤，血管壁削弱和僵硬，血脑屏障（BBB）渗透性和恶化的细胞因子生产是与脑血管衰老相关的标志性改变，并且在MFS中很普遍。这些衰老和MF的表现是由于变化的生长因子-BETA（TGF-β）信号传导而发生的。在小鼠，FBN1突变会诱导6个月（6M）年龄的血管功能障碍。这个容易访问的模型具有在290多个研究中使用，其中只有两个已经解决了脑血管造型，证明脑中动脉（MCA）壁/管腔肥大，基质金属蛋白酶（MMP）增加的增加脉络丛中的MCA，BBB渗透性和TGF-β细胞因子和MMP产生。这些结果和该实验室的数据表明，在该模型中，发生脑血管衰老的增加类似于正常衰老，但加速速度。这导致了以下假设：FBN1突变会加速衰老相关的脑血管功能和神经行为改变。为了测试这一点，FBN1 +/- 将评估6M的小鼠，C57BL/6小鼠在6（CTRL）和12m（WT）的小鼠进行脑血管变化评估通过这些目的和神经病理学：1）测量血浆中TGF-β信号分子的表达和FBN1 +/-鼠标模型中的海马。 2）评估脑血管结构和功能 FBN1 +/-鼠标模型。 3）检查FBN1 +/-小鼠模型中的神经病理学形态和功能。一个强大的心理团队支持该建议，并提供专业知识和资源。来自此实验室支持的数据 FBN1突变在加速脑血管衰老和神经病理学中起着至关重要的作用，从而增加神经系统损伤（例如轻度脑损伤）后，脆弱性结果脆弱的风险。影响：这是FBN1突变的首次投资，是加速脑血管衰老的贡献和功能障碍，其中TGF-β信号通路可能揭示了机制和治疗靶标的预防和保护MFS中增加血管功能障碍和神经病理学，类似结缔组织障碍和人口老龄化。