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.
The proposed research is relevant to public health because gait abnormalities, which are present in over 30% of older adults, increase risk of falls with often tragic consequences. The present application focuses on an important and potentially preventable (yet under-studied) cause of age-related gait and balance abnormalities: cerebral microbleeds caused by hypertension-induced rupture of small cerebral vessels. The discovery of the cellular mechanisms responsible for increased vulnerability to cerebral microhemorrhage in the elderly is ultimately expected to increase understanding of the pathogenesis of gait and balance abnormalities and will lead to the development of novel therapeutic interventions for the prevention; thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of disability in the elderly.
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