The basic understanding of the immune system has undergone a substantial paradigm shift in the past decade as an awareness of the power and influence of the innate immune system has emerged. Essentially, it is now being recognized that the nature of the first response to invasion has significant influence in determining the nature of the subsequent adaptive immune response. That is, it is this first response that assesses the level of danger of a particular intrusion or injury and initiates a program of protection.
My laboratory is focused on the role of specific elements of the innate immune system in host defense and in maintaining a balance of protective responses in the host. We have been elucidating mechanisms by which phagocytic cells regulate induction of an appropriate adaptive response. As phagocytic cells ingest distinct particles specific gene expression programs are initiated that influences the induction of an appropriate immune response. Thus, we are investigating the downstream events such as cytokine expression resulting from the interaction of pattern recognition signals in the context of various particles targeted for ingestion.
The second major research area is the investigation of the role of complement activation and subsequent inflammation in Alzheimer’s Disease. The neuropathological structures that are the hallmark of Alzheimer's disease (AD) include senile plaques composed of a proposed pathogenic peptide fragment, beta-amyloid (A-Beta), neurofibrillary tangles and loss of neurons. Using mouse models of AD, we have evidence consistent with the hypothesis that complement activation and subsequent inflammatory events contribute to the pathogenesis of dementia in AD, and are currently testing candidate therapeutics to prevent or slow the progression of pathogenic events that lead to Alzheimer’s Disease in mouse models. In addition, we postulate that C1q may be a response to injury that could play a protective role in the early stages of disease by enhancing the clearance of cellular debris, altering the effects of the amyloid peptide on microglia, and/or providing direct neuroprotective effects. We use novel mouse models and cell isolation procedures to assess the molecular basis of these effects to identify targets for therapeutic intervention in neurodegenerative diseases.
Key Research Areas:
Innate immunity, inflammation, complement, Alzheimer's disease, cell surface receptors