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:
  • 金额:
    $ 5.01万
  • 依托单位:
  • 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

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.
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