Masashi Kitazawa, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Inclusion body myositis (IBM) is the leading age-related skeletal muscle disorder, yet its etiology remains unknown, nor do effective treatments exist. We developed novel transgenic models that mimic IBM-like motor deficits and pathology, including Aft accumulation and tau phosphorylation in skeletal muscle. This proposal investigates the genetic and pharmacologic factors that modulate the severity of IBM-like pathology in transgenic mice. Our preliminary data indicate that the accumulation of Aft plays a pivotal role in its pathogenesis. Consequently, factors that augment Aft, such as inflammation, exacerbate the phenotype, whereas we propose that interventions that reduce Afi may be an effective therapeutic strategy to delay or cure IBM. The first two aims are continuation of current studies. Aim 1 determines the pathologic effect of inflammatory responses in skeletal muscle on Aft and tau and also evaluate any anti-inflammatory agents modulate these IBM-like pathology. In aim 2,1 will utilize our transgenic IBM models to determine if Aft immunotherapy ameliorates the motor deficits and myopathology. We will investigate the effect of active immunization as a potential treatment for IBM; the outcome of this study may justify the initiation of a human clinical trial with IBM patients. The last aim (aim 3) focuses on the molecular link between myopathy and dementia, based on the current finding of genetic link between these diseases. I will generate novel transgenic mice harboring a clinical mutation in the valosin-containing protein (VCP) gene, responsible for IBM/Paget disease/frontotemporal dementia. Mutations on VCP may be involved in the abnormal accumulation of disease-relevant proteins found in both IBM and some neurodegenerative disorders. Thus, the mouse models will be useful both for therapeutic evaluation and for investigating any shared molecular mechanisms underlying the pathogenesis of these distinct diseases. This latter point is worth emphasizing as many dementia-related proteins accumulate in damaged muscle fibers in IBM, suggesting that there may be a coordinated cellular response to these proteins; thus, information learned from these models may be applicable to dementias like Alzheimer disease. Furthermore, providing multiple lines of disease models may accelerate the research progress in the field. Through this application, we hope to advance the understanding of IBM as well as dementias and evaluate potential therapeutic strategies for IBM. [unreadable] [unreadable] [unreadable] [unreadable]

Mutations in valosin-containing prote in (VCP) cause a rare complex disorder called inclusion body myopathy associated with Paget disease ofthe bone and frontotemporal dementia (IBMPFD). The exact underlying molecular and cellular pathogenic a nd degenerative mechanisms mediated by mutant VCP remain unl

DESCRIPTION (provided by applicant): Environmental and occupational copper exposure has long been considered one of the environmental risk factors for Alzheimer's disease (AD). However, the late life impact of the chronic copper (Cu) exposure and its mechanisms of action in the central nervous system (CNS) have not been fully elucidated. While its direct toxicity on neurons and interaction to amyloid-beta (Aß) species are currently been studied, its chronic impact on other non-neuronal cells in the CNS has been overlooked. We hypothesize that a chronic environmentally-relevant Cu exposure impairs the activation of microglial phagocytosis and neuroinflammatory responses, promoting a pathological buildup of Aß species, synaptic loss and cognitive decline. The objective of this study is to determine whether the copper-mediated functional impairment of glial activity promotes neurodegeneration and AD neuropathology in vivo. To achieve our goal, we propose to apply two novel techniques to determine microglia- and astrocyte-specific transcriptome dynamics following chronic Cu exposure in vivo. Our proposed project will uncover the critical pathogenic impact of Cu exposure on microglia, astrocytes and neuroinflammation, and the underlying molecular mechanism by which glial dysfunction leads to the onset and progression of AD in a temporal manner.

PROJECT SUMMARY/ABSTRACT Exposure to automobile exhaust and wastes generated by industrial combustion through contaminated air is one of the most common environmental exposures among the general public, and long-term exposure to such polluted air and its main constituent, fine and ultrafine particulate matter (PM), has long been recognized as a major risk factor for cardiovascular morbidity and mortality. Notably, recent population-based epidemiological studies identify PM's significant influence on cognitive function in humans, and indicate it as an increased risk for developing Alzheimer's disease (AD). These findings suggest that exposure to PM causes lifelong impact on the central nervous system and substantial neurotoxicity, giving rise to accelerated cognitive decline and possibly the development of AD neuropathology. However, research has yet to fully elucidate the biological mechanisms of PM-induced neurotoxicity, at the molecular and cellular levels, or to elucidate functional, morphological, anatomical, and/or pathological changes leading to cognitive decline and increased risk for AD. Given our expertise and recently emerging evidence in the field, we hypothesize that the exposure to PM perturbs dendritic spines and promotes the buildup of toxic amyloid-beta (A?) species by aggravated microglial activation and neuroinflammation. The proposed research will rigorously assess the changes in dendritic spine morphology, A? buildup, microglial activation, and inflammatory profiles in mice exposed to environmentally- relevant PM and determine the microglia's prime role in PM-induced neurotoxicity by ablating them. The proposed project is significant as we aim to identify microglia as a key mediator of inhaled PM-induced neurotoxicity and reveal inhaled PM's biological impact on cognitive decline and the risk for AD. Deciphering cellular cascades triggered by exposure to environmental PM will exhibit highly intrinsic merit toward understanding the environmental impact on brain health and will contribute to improving public awareness of the risk of exposure to environmental contaminants. This project has significant translational value, as an improved understanding of the biological mechanisms by which exposure to PM influences cognitive decline will pave the way for more effective preventive and therapeutic measures.