Cerebral microhemorrhages and gait dysfunction in aging

衰老过程中的脑微出血和步态功能障碍

基本信息

批准号：
9974451
负责人：
ZOLTAN Istvan UNGVARI
金额：
$ 29.73万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974451
关键词：
Address Affect Aging Antioxidants Blood Vessels Caliber Cerebrovascular Disorders Cerebrum Clinical Clinical Research Collagen Complex Consequentialism Data Development Elderly Equilibrium Etiology Extracellular Matrix Fractals Functional disorder Gait Gait abnormality Genetic Goals Hemorrhage Homeostasis Human Hypertension Impaired cognition Impairment Individual Inhibition of Matrix Metalloproteinases Pathway Injury Institutionalization Knowledge Lead Link MMP3 gene Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Methods Mission Mitochondria Motor Mus Neurologic Deficit Neurons Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Pattern Phenotype Positioning Attribute Pre-Clinical Model Predisposition Prevention Prevention approach Preventive Intervention Production Property Public Health Reactive Oxygen Species Research Risk Factors Role Rupture Scheme Severities Structure Testing Therapeutic Intervention United States National Institutes of Health White Matter Disease Work age related aged attenuation base catalase cerebral microbleeds cerebral microvasculature cerebrovascular cerebrovascular lesion clinically relevant disability disability burden equilibration disorder experience fall risk falls gait examination innovation mouse model novel novel therapeutic intervention overexpression preservation prevent

项目摘要

Gait and balance disorders are among the most common causes of falls in older adults. Recent clinical studies identify a novel microvascular etiology that contributes to gait abnormalities in the elderly: cerebral micro- hemorrhages (CMHs). In the elderly hypertension is the major risk factor for CMHs, which are associated with rupture of small intracerebral vessels and progressively impair neuronal function. Although CMHs affect one third of older individuals, their pathogenesis remains completely obscure and there are no therapeutic interven- tions available for prevention. The central hypothesis of this application that hypertension exacerbates mito- chondrial oxidative stress in aged cerebral vessels, which results in activation of MMPs, collagen degradation and remodeling of the extracellular matrix, promoting microvascular fragility. The resulting CMHs impair fine motor coor- dination, promoting gait and balance abnormalities. Our prediction based on this hypothesis is that attenuation of mitochondrial oxidative stress or inhibition of MMP activation will protect the structural integrity of cerebral vessels preventing the development of CMHs and preserving normal gait and balance function in aging. Based on our ex- tensive experience in this field and our preliminary data, we are well positioned to test our hypotheses using innova- tive mouse models of CMHs and advanced methods of gait analysis in mice. Specific Aims: 1) Determine how the number, size and localization of CMHs impact gait and balance function in aged mice. The proposed studies will use novel, sensitive and translationally highly relevant methods to characterize CMH-related abnormalities of fractal properties of gait cycle and establish the link between the severity, number and localization of the CMHs and gait abnormalities in aged mice. The predictive power of gait abnormalities to CMH-related cognitive impairment will al- so be determined. 2) Determine how age-related changes in extracellular matrix composition, MMP activation and CMHs relate. Our hypothesis is that aging exacerbates activation of MMPs, collagen degradation and remodeling of the extracellular matrix, promoting microvascular fragility and CMHs. 3) Determine the role of mitochondrial oxi- dative stress in increased susceptibility to CMHs in aging. Our hypothesis is that overexpression of catalase tar- geted to the mitochondria or treatment with the mitochondria-targeted antioxidant on structural integrity of cerebral vessels. Together, the proposed studies will identify a fundamental mechanism responsible for age-related ex- acerbation of CMHs, and thus vascular-induced neurological deficits —increased mitochondria-derived ROS production and consequential degradation of cerebrovascular structural integrity. These outcomes will have an important positive impact, since they will enable us to develop novel, translationally relevant interventional strategies for prevention of CMHs, protecting gait and balance function in the elderly.

步态和平衡障碍是老年人跌倒的最常见原因之一。确定了一种导致老年人步态异常的新微血管病因：脑微血管在老年人中，高血压是 CMH 的主要危险因素，这与出血有关。尽管 CMH 会影响脑内小血管的破裂并逐渐损害神经功能。三分之一的老年人，其发病机制仍然完全不清楚，并且没有治疗干预措施该应用的中心假设是高血压会恶化线粒体。老化脑血管中的软骨氧化应激，导致 MMP 激活、胶原蛋白降解和细胞外基质的重塑，促进微血管脆性，从而损害精细运动协调能力。我们基于这一假设的预测是，饮食、促进步态和平衡异常的减弱。线粒体氧化应激或抑制MMP激活将保护脑血管的结构完整性预防 CMH 的发展并在衰老过程中保持正常步态和平衡功能。凭借在该领域的丰富经验和我们的初步数据，我们有能力利用创新来检验我们的假设 CMH 的活性小鼠模型和小鼠步态分析的高级方法具体目标： 1) 确定如何 CMH 的数量、大小和定位影响老年小鼠的步态和平衡功能。使用新颖、灵敏且转化高度相关的方法来表征与 CMH 相关的分形异常步态周期的特性，并建立 CMH 的严重性、数量和定位与步态之间的联系老年小鼠的步态异常对 CMH 相关认知障碍的预测能力也将同样如此。 2) 确定细胞外基质成分、MMP 激活和年龄相关的变化如何。我们的假设是，衰老会加剧 MMP 的激活、胶原蛋白的降解和重塑。细胞外基质，促进微血管脆性和 CMH 3) 确定线粒体氧化的作用。衰老过程中对 CMH 的易感性增加的与生压力有关。我们的假设是过氧化氢酶焦油的过度表达。进入线粒体或使用线粒体靶向抗氧化剂治疗大脑结构完整性总之，拟议的研究将确定导致与年龄相关的前病变的基本机制。 CMH 的加剧，从而导致血管诱发的神经功能缺损——线粒体衍生的 ROS 增加这些结果将产生脑血管结构完整性的产生和随之而来的退化。重要的积极影响，因为它们将使我们能够开发新颖的、与转化相关的干预措施预防 CMH、保护老年人步态和平衡功能的策略。