Discovering novel mechanisms for aging-related dementia: probing medin and abeta vasculopathy

发现衰老相关痴呆的新机制:探索医学和阿贝塔血管病

基本信息

  • 批准号:
    9352441
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-04-01 至 2021-03-31
  • 项目状态:
    已结题

项目摘要

Abstract There remains no effective treatment to reverse aging-related dementia disorders (ARDD), including Alzheimer’s disease (AD). Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with ARDD and AD and that vascular dysfunction leading to cerebral hypoperfusion is critical in the early stages of AD. Prior investigators showed that medin, a 50 amino acid peptide found in vascular smooth muscle layer, is the most common amyloid protein in humans with progressive vascular deposition with aging. Medin was implicated as a cause of vessel wall degenerative changes associated with vascular aging, but its role in aging-related cerebrovascular dysfunction is not known. We have preliminary data in both adipose and leptomeningeal arterioles that medin as well as β-amyloid (Aβ), a peptide involved in AD, induce endothelial dysfunction through oxidative stress and reduced nitric oxide bioavailability and that medin induces strong pro- inflammatory response in endothelial cells. Our overall goal is to test the hypotheses that medin amyloid protein, alone or synergistically with Aβ, is a significant, but unrecognized, cause of ARDD by inducing human brain microvascular dysfunction and inflammation. For Aim 1 we will probe the role of medin amyloid and its interaction with Aβ in causing aging-associated human cerebrovascular dysfunction and cognitive dysfunction. We will measure extent of cerebrovascular medin amyloidosis in the elderly and its relationship to cognitive dysfunction and Alzheimer’s disease using tissue and associated pre-mortem clinical data from Sun Health Research Institute Brain Donation Program. We will also probe mechanisms by which medin amyloid induces cerebrovascular dysfunction in ex-vivo rapid autopsy human brain leptomeningeal arterioles, focusing on the role of nitric oxide dysregulation, oxidative stress and induction of vascular inflammation. We will study the interaction between medin and Aβ in inducing human cerebrovascular dysfunction, vascular inflammation and cognitive dysfunction. For Aim 2, we will validate whether peripherally obtained subcutaneous adipose arterioles are useful surrogates to brain cerebrovascular arterioles in studying medin and Aβ-induced microvascular dysfunction. The proposal will have impact in the potential discovery of a novel mechanism that could link vascular aging and cognitive dysfunction in the elderly. Furthermore, the use of a novel and unique human brain tissue model would enhance the translation relevance of the findings to the human condition.
Abstract There remains no effective treatment to reverse aging-related dementia disorders (ARDD), including Alzheimer’s disease (AD). Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with ARDD and AD and that vascular dysfunction leading to cerebral hypoperfusion is critical in the early stages of AD. Prior investigators showed that medin, a 50 amino acid peptide found in vascular smooth muscle layer, is the most common amyloid protein in humans with progressive vascular deposition with aging. Medin was implicated as a cause of vessel wall degenerative changes associated with vascular aging, but its role in aging-related cerebrovascular dysfunction is not known. We have preliminary data in both adipose and leptomeningeal arterioles that medin as well as β-amyloid (Aβ), a peptide involved in AD, induce endothelial dysfunction through oxidative stress and reduced nitric oxide bioavailability and that medin induces strong pro- inflammatory response in endothelial cells. Our overall goal is to test the hypotheses that medin amyloid protein, alone or synergistically with Aβ, is a significant, but unrecognized, cause of ARDD by inducing human brain microvascular dysfunction and inflammation. For Aim 1 we will probe the role of medin amyloid and its interaction with Aβ in causing aging-associated human cerebrovascular dysfunction and cognitive dysfunction. We will measure extent of cerebrovascular medin amyloidosis in the elderly and its relationship to cognitive dysfunction and Alzheimer’s disease using tissue and associated pre-mortem clinical data from Sun Health Research Institute Brain Donation Program. We will also probe mechanisms by which medin amyloid induces cerebrovascular dysfunction in ex-vivo rapid autopsy human brain leptomeningeal arterioles, focusing on the role of nitric oxide dysregulation, oxidative stress and induction of vascular inflammation. We will study the interaction between medin and Aβ in inducing human cerebrovascular dysfunction, vascular inflammation and cognitive dysfunction. For Aim 2, we will validate whether peripherally obtained subcutaneous adipose arterioles are useful surrogates to brain cerebrovascular arterioles in studying medin and Aβ-induced microvascular dysfunction. The proposal will have impact in the potential discovery of a novel mechanism that could link vascular aging and cognitive dysfunction in the elderly. Furthermore, the use of a novel and unique human brain tissue model would enhance the translation relevance of the findings to the human condition.

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Raymond Quezon Migrino其他文献

Raymond Quezon Migrino的其他文献

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{{ truncateString('Raymond Quezon Migrino', 18)}}的其他基金

Anti-medin immunotherapy for vascular aging and related dementias
针对血管老化和相关痴呆的抗 Medin 免疫疗法
  • 批准号:
    10724869
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Discovering novel mechanisms for aging-related dementia: probing medin and abeta vasculopathy
发现衰老相关痴呆的新机制:探索医学和阿贝塔血管病
  • 批准号:
    9898308
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Discovering Novel Mechanisms and Treatment for Aging-Related Dementia: Probing Medin and Abeta Vasculopathy
发现衰老相关痴呆的新机制和治疗方法:探索 Medin 和 Abeta 血管病
  • 批准号:
    10359074
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Discovering Novel Mechanisms and Treatment for Aging-Related Dementia: Probing Medin and Abeta Vasculopathy
发现衰老相关痴呆的新机制和治疗方法:探索 Medin 和 Abeta 血管病
  • 批准号:
    10620132
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Human vascular model to study Alzheimer's Disease
研究阿尔茨海默病的人体血管模型
  • 批准号:
    8769904
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Human vascular model to study Alzheimer's Disease
研究阿尔茨海默病的人体血管模型
  • 批准号:
    8923141
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Nanoliposome-based Treatment of Amyloid Protein (AL) Toxicity
基于纳米脂质体的淀粉样蛋白 (AL) 毒性治疗
  • 批准号:
    8543427
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Nanoliposome-based Treatment of Amyloid Protein (AL) Toxicity
基于纳米脂质体的淀粉样蛋白 (AL) 毒性治疗
  • 批准号:
    8803354
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Vascular dysfunction and oxidative stress in primary amyloidosis
原发性淀粉样变性的血管功能障碍和氧化应激
  • 批准号:
    7585890
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Vascular dysfunction and oxidative stress in primary amyloidosis
原发性淀粉样变性的血管功能障碍和氧化应激
  • 批准号:
    7844940
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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