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. One major effort is in elucidating mechanisms that regulate phagocytosis, a defense mechanism that results in the elimination and killing of infectious agents and is the first step in antigen processing and presentation necessary for an antibody or T cell mediated adaptive response. Phagocytosis of particles is regulated by host proteins that recognize pathogen associated molecular patterns. One such family of host proteins, called defense collagens, consists of lectins such as mannose binding lectin (MBL) and ficolin, as well as the complement protein C1q and the pulmonary surfactant protein A (SPA). This family of proteins mediates a potentially very advantageous attribute that should limit the infection of microbes, and as a result we are investigating the molecular pathways involved in the enhancement of this function, with the potential for manipulating the system in a clinically advantageous way. This may be particularly important in neonates, individuals immunocompromised by genetics or disease, or individuals encountering new environments and thus potential pathogens. In addition, since the cellular signals generated by phagocytic cells as they ingest specific particles for antigen presentation influence the subsequent immune response, the influence of these proteins on the generation of immune responses to vaccination is also of interest. Thus, we are investigating the down stream events such as cytokine expression resulting from of these proteins to phagocytic cells. A membrane glycoprotein, originally designated C1qRp (the C1q receptor that enhances phagocytosis) has been isolated and shown to influence the phagocytic activity in response to these defense collagens. This surface receptor, now also identified as CD93, is also highly expressed on endothelial cells, and thus we are currently exploring how this molecule signals the cell and what physiologic role of this molecule plays in times of challenge. Another major research area in the laboratory 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. We are currently testing the hypothesis that complement activation and subsequent inflammatory events contribute to the pathogenesis of dementia in AD. If so, a therapeutic reagent that would tightly bind A-Beta near the C1q interaction site, such that the activation of complement by fibrillar amyloid would be sterically or otherwise inhibited, could be an effective treatment to prevent or slow the progression of pathogenic events that lead to Alzheimer's Disease. In addition, we also 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 and/or altering the effects of the amyloid peptide on microglia. Three models are used to test these hypotheses: in vitro mixed neuron and glia cultures, organotypic slice cultures and transgenic animals.
2228 McGaugh Hall
2419 McGaugh Hall