The Catz Laboratory

Scientific Interest

The mechanism underlying neutrophil exocytosis

Exocytosis in neutrophils is a crucial event in inflammation and innate immune response. Neutrophils contain four types of secretory organelles that hold a variety of specialized proteins which are essential for the microbicidal activity of these cells. The hierarchy that characterizes the secretory process of these granules correlates with the different roles of their cargo proteins in the processes of adhesion, migration, chemotaxis, phagocytosis and the production of reactive oxygen species. Tight regulation of the exocytic process is especially necessary in neutrophils because unrestricted release of the toxic content of their granules is injurious to the host.

The small GTPase Rab27a plays a central role in the regulation of exocytosis. Rab27a is the only Rab directly associated with a human genetic disease, Griscelli syndrome (GS). Patients with GS develop an immunodeficiency disorder characterized by malfunction of cytotoxic T-lymphocytes and impaired natural killer cell function. We have recently shown that Rab27a and its counterpart effectors ¬¬coordinate the exocytic dynamics of neutrophil granules. Our future studies aim to elucidate the differential mechanisms underlying the regulation of granule mobilization to the plasma membrane or to the phagosome using genetic and cellular biology approaches. Our long-term goal is to develop molecular therapeutic strategies to prevent uncontrolled release of neutrophil granule cargo proteins.

Vesicular trafficking in lysosomal storage disease (LSD)

LSD are genetic or acquired diseases characterized by anomalous accumulation of metabolites in the lysosomes. Increased levels of intralysosomal metabolites leads to cell malfunction and cell death. We have special interest in developing strategies directed at upregulating the vesicular trafficking pathways of cells that have accumulated metabolites in their lysosomes to restore normal cellular function and prevent cell death. We are currently exploring several trafficking pathways and utilizing high-throughput screening approaches to identify potential novel therapies for the treatment of LSDs.

Understanding Toll-like receptor signaling to improve the innate immune response to polymicrobial infections

Increasing evidence indicates the importance of mixed bacterial infections in the modulation of the pathogenicity of the individual bacterial strains, the concomitant host response, and the course and outcome of infectious diseases. Evidence suggests that during mixed infections the pathophysiology of one microorganism is affected by the co-infecting bacteria. Little is known about how the microorganisms modulate the host immune response during mixed infections.

Our research is directed at understanding the molecular mechanisms that regulate the neutrophil response during mixed infections. In particular, we examine the TLR-signaling involved in this regulation, and dissect the signaling mechanisms that mediate synergism or tolerance during mixed infections.

Other scientific Interests

• Neutrophil extracellular traps (Nets)
• NADPH Oxidase
• Immunological synapse
• Exocytosis in non-inflammatory cells (prostate carcinoma cells, RPE)
• Prostate cancer
• Transcriptional Regulation
• Signal transduction and phosphoinositides