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The Catz Laboratory

Scientific Interest

The mechanism underlying neutrophil function  

Neutrophils are the first line of cellular defense of the innate immune system. They kill microorganisms in the phagosome or by releasing microbicidal products into the extracellular space. In resting neutrophils, these microbicidal molecules are segregated in vesicles to protect the host from uncontrolled activation. 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 and neutrophil extracellular traps (NETs). Tight regulation of the neutrophil function is essential in order to control both a proper response to infection and inflammation.

 

Vesicular trafficking mechanisms of immune cells. The importance of Rab GTPases

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, the immunodeficiency Griscelli syndrome (GS). Deficiency of the Rab27a effector Munc13-4 is also associated with the human disease Familial Hemophagocytic Lymphohisticytosis type 3 (FHL-3). Patients with GS and FHL-3 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 studies aim to elucidate the differential mechanisms underlying the regulation of granule mobilization to the plasma membrane and to the phagosome in neutrophils using genetic and cellular biology approaches. One of our long-term goals is to develop molecular therapeutic strategies to prevent uncontrolled release of neutrophil granule cargo proteins to prevent inflammation without affecting the innate and adaptive immune responses.

Drug Discovery for the control of vesicular trafficking mechanisms in cellular processes of medical importance

Intracellular vesicular transport is essential for nearly all aspects of cellular physiology and plays a central role in the regulation of cellular homeostasis, cell division and immunity. Most vesicular transport processes are regulated by Rab proteins, monomeric GTPases of the Ras superfamily that act as membrane organizers. Different Rab proteins are distributed in specific cell compartments and, together with their effectors, synchronize and regulate vesicle motility, docking and fusion to specific acceptor membranes.

My laboratory is interested in the study of Rab GTPases and effector molecules and their role in trafficking mechanisms. In our studies, we utilize animal models and cellular systems with the common objective of elucidating the role of small Rab GTPases in physiology and disease. In addition, we have developed unique quantitative systems biology methods for the analysis of granule dynamics and positioned ourselves as one of the few laboratories studying the processes that control vesicular trafficking mechanisms preceding exocytosis in granulocytes. We are also interested in vesicular trafficking mechanisms associated with human disease including inflammation, diabetes, age-related macular degeneration (AMD) and lysosomal storage disorders.

We have developed and implemented high-throughput screening assays to identify small-molecule inhibitors and activators of vesicular trafficking and found specific modulators that will be utilized to answer mechanistic questions and to explore in vivo effects associated with clinically relevant processes including inflammation and sepsis, diabetes, age-related macular degeneration (AMD), lysosomal storage disorders and endocytic pathway-associated processes including viral entry and phagocytosis. The results of our research should uncover the molecular mechanisms regulating vesicular transport and lead to effective strategies for the treatment of human disease.

 

Vesicular trafficking in lysosomal storage diseases (LSDs)

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 identified vesicular trafficking mechanisms that, when impaired, are associated with the development of abnormal levels of endoplasmic reticulum stress (ER stress) in LSDs. 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 infections

Increasing evidence highlights the importance of the neutrophil response to 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. We perform research directed at understanding the signaling pathways that control the molecular mechanisms regulating the neutrophil response to soluble and particulate stimuli from pathogens during infections. In particular, we have examined the TLR-signaling involved in this regulation, and have dissected the signaling mechanisms that mediate synergism or tolerance during neutrophil activation. In this context, we have identified key roles for IRAK-4 and PI3-kinase but not TRIF during LPS-induced neutrophil activation.   

 

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 metabolism