Molecular Pathogenesis

The MP program is perhaps the broadest of the research programs in the Skirball Institute. It includes a large proportion of NYU's Immunology community, which has a rich tradition, and its members have taken the lead in establishing a new graduate program in immunology and host defense mechanisms. The MP program's immunology laboratories study diverse problems in the areas of lymphocyte signal transduction, immunological synapse formation, leukocyte trafficking, VDJ recombination, and innate immune responses. Immunologists in the MP program also study medically relevant problems such as the mechanisms of HIV pathogenesis, allergic disease, autoimmunity, and lymphomagenesis. Other MP laboratories are investigating telomere maintenance, protein misfolding, bacterial virulence, and genomic instability while striving to understand human afflictions as diverse as diabetes, cholesterol toxicity, cancer, and aging. Close collaborations of the laboratories in the MP program with groups in the other Skirball research programs have been instrumental in studying the genetic basis of the unfolded protein response, the role of lipid phosphatases in vesicular traffic, and the roles of chemokine receptors in morphogenesis of different organ systems. Members of the MP program have appointments in NYU School of Medicine departments of Cell Biology, Medicine, Microbiology, Pathology and Pharmacology.

Administrative Assistants: Richard Stout, Sandra Anyata, Jeff Blenker,

Littman Lab

Our laboratory is interested in the molecular mechanisms involved in the differentiation of T lymphocytes into distinct functional subsets, in the signaling pathways involved in T cell activation, and in the migration of T cells and antigen presenting cells to lymphoid organs and sites of inflammation. We also study the function of progenitor cells required for development of secondary lymphoid organs. Our investigation of T cell lineages has led us to study mechanisms by which stable states of gene expression are established and maintained during development. Our other major interest is in elucidating the mechanisms by which the Human Immunodeficiency Virus is transmitted and damages the immune system. Our goals are to identify human host factors required for HIV replication and pathogenesis and to engineer mice permissive for HIV infection and replication.

Ron Lab

The folding state of polypeptides is easily perturbed by adverse conditions. Failure to properly fold polypeptides into the appropriate three-dimensional structure impacts directly on the ability to synthesize useful proteins and introduces inefficiency into the cell's economy. But protein malfolding has an additional consequence: structures elaborated by polypeptides that fail to attain their proper three dimensional fold may exert a deleterious effect on cellular function. This process, also referred to as "proteotoxicity," appears to be particularly important to the fate of non-renewable cells of long-lived organisms in which accumulating malfolded proteins can exert their deleterious effects over extended periods of time. The hypothesized contribution of such "proteotoxins" to cellular aging fits our intuitive notions of aging as a time and use-dependent process. The progressive aging of the human population has led to an increase in the incidence of diseases hypothesized to be associated with various forms of proteotoxicity. These include not only the classic examples of the Amyloidoses, Prion disorders, Alzheimer's disease and various forms of Parkinsonism - in all of which the accumulation of abnormal proteins can be readily observed - but also, we hypothesize, others such as type-II diabetes mellitus in which low-levels of protein malfolding in the secretory pathway, over time, might contribute to exhaustion of the insulin-producing islet beta cell.

Burakoff Lab

The main focus in our laboratory is the study of signaling cascades that govern T cell activation, function, and regulation. We are particularly interested in the signaling molecules and pathways that lead to the modulation of the effector functions of both CD4+ and CD8+ T cells. While activation signals are essential and required, the negative signaling or negative regulation of positive signals are as much essential for the normal growth and function of the cell. One of the major interests in the laboratory is to understand how the signals from T-cell antigen receptor (TCR) are negatively regulated. This study has lead to the elucidation of function of various signaling molecules like Gab2, Crk, Cbl, and HPK1.

Other areas of investigation include: 1) the molecular assembly of lipid rafts and its role in signaling; 2) the effector functions of CD8+ T cell that govern graft vs. host (GVH) and graft vs. leukemia (GVL) effect in transplant models; 3) the signaling cascades involved in the altered peptide ligand (APL) signaling in a model system to understand the regulation of tolerance; 4) the role of HPK1 in maturation of Dendritic cells (DC's).

Diefenbach Lab

Laboratory of Innate Immune Recognition

Genetic defects in innate immune functions lead to increased susceptibility to infection, an increased incidence of tumors and a reduced potency of the adaptive immune response. These findings led to two paradigms for the function of the innate immune system. First, the innate immune system establishes a highly efficient barrier against tumors and infections. Second, innate immune activation is a requirement for an efficient adaptive immune response. Our research focuses on understanding the molecular mechanisms underlying both of these processes.

Until recently, the molecular mechanisms of innate immune recognition have been elusive. Over the last five years, studies of two novel receptor/ligand systems (the Toll-like receptors that directly recognize bacterial and viral products and the NKG2D receptor that recognizes class I MHC-like molecules selectively upregulated by abused cells) have given us a glimpse into how innate immune recognition might protect us from various forms of disease. Recent data would suggest that cells of the innate immune system express a number of invariant immunoreceptors that recognize transformed and infected cells. Still, though, the nature and the biological role of most receptors expressed by cells of the innate immune system remain unknown. One focus of our research is to define novel receptors expressed by cells of the innate immune system and to identify their ligands. We use gene targeting and transgenic techniques in mice, as model systems, to study the role of these receptors in various human diseases. These studies have broad ramifications for our understanding of how the innate immune system protects us from disease.

Early stages of inflammation or infection result in activation of an innate immune response, and this is generally followed by activation of T and B cells, which mount the highly specific adaptive immune response. Effective adaptive immune responses do not just follow an innate immune response, they require them. We study the role of innate immune cells (dendritic cells/macrophages, NK cells, NKT cells) in the priming of T and B cell responses to pathogens and tumors as well as in autoimmune disorders. These studies may reveal how to intelligently promote activation of cells associated with the adaptive immune system and, thus, enhance previously existing therapeutic interventions or unlock entirely new strategies.

Dustin Lab

The focus of our lab is to understand basic aspects of T cell activation, particularly the role of physical interaction of T cells and antigen presenting cells. We have developed a technology for studying receptor-ligand interactions in a physiological, but highly controllable, system using supported planar bilayers to replace one of the interacting cells. Using this approach we described and quantified formation of the immunological synapse by T cells in response to supported planar bilayers containing adhesion molecules and MHC-peptide complexes (antigen). We continue to use this approach to address basic questions in T cell receptor signaling with the synapse and the integration of co-stimulatory signaling.

A second major area is to understand the manner in which environmental signals are integrated with signals from the T cell receptor in secondary lymphoid tissues and other tissue sites. We study mice in vivo to gain new insights into the motivation and regulation of T cells and how signals are integrated. Having real time molecular, cellular and tissue analysis going forward in parallel will provide opportunities for formulating and testing hypotheses at many levels of organization covered by the immune response.

Lafaille Lab

Although most normal immune responses against pathogens require the action of T-lymphocytes, their improper control lies at the heart of two types of disease: autoimmunity and allergy. Our laboratory uses transgenic and knockout mice to study the molecular mechanisms responsible for the normal control of T-lymphocyte reactivity and the changes that occur when T-lymphocytes become either aggressive against self antigens or inappropriately reactive against substances (allergens) normally present in the environment.

Currently, we are examining the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, in transgenic mice bearing antimyelin basic protein (MBP) T-lymphocytes. Mice harboring large numbers of anti-MBP T-lymphocytes in addition to other lymphocytes seldom develop EAE spontaneously. However, when these mice are crossed with RAG-l KO mice, thereby producing only anti-MBP T-lymphocytes, they all develop spontaneous EAE. The sharp contrast in susceptibility to EAE between the two types of anti-MBP transgenic mice, one carrying regulatory lymphocytes and the other not, enables us to pursue, identifying, and characterize those cells. We also focus on a transgenic mouse model for asthma to determine in vivo the factors controlling the synthesis of important interleukins involved in the asthmatic process, such as IL-4 and IL-5, and the increased production of immunoglobulin E.

Novick Lab

Staphylococcus aureus, a major nosocomial pathogen, causes a wide variety of infections, from simple abscesses to fatal sepsis, plus toxinoses, such as food poisoning and toxic shock syndrome. S. aureus produces and secretes thirty or more specific pathogenicity factors that interfere with host defenses. Its pathogenic versatility is compounded by its ability to develop resistance to new antibiotics almost as fast as they are introduced.

We have identified, sequenced, and characterized a global regulator, agr, that is the major regulatory element in a precisely orchestrated temporal program of virulence gene expression in vitro in S. aureus. Agr consists of a 2-component signal transduction pathway, an autoinducing octapeptide (AIP) that serves as its ligand, and a regulatory RNA that controls target gene expression. There are 4 or more groups of S. aureus strains that synthesize different AIPs; these activate agr expression within their group but inhibit agr expression in the other groups. We find that one of the AIPs can block infection by a heterologous strain in a mouse subcutaneous abscess model. We now study the biochemistry of AIP processing, the structure and function of the regulatory RNA, the expression of virulence factors in vivo, and the use of inhibitory peptides for antibacterial therapy.

Roth Lab

Most of us tend to think of genomes as static entities, and consider alterations in DNA only when speaking of mutations or damage that must be repaired. But genomes are surprisingly plastic. Chromosomal breakage, a dangerous event that has triggered the evolution of numerous double strand break (DSB) repair pathways, is actually necessary for immune system development. B and T lymphocytes recognize antigens through receptor proteins whose genes are assembled from different DNA segments by a process known as V(D)J recombination. This gene-shuffling entails introducing DSBs in millions of lymphocyte precursors each day. We are interested in the mechanisms that preserve genomic stability in the face of all this cutting and pasting. Understanding the mechanisms involved in V(D)J recombination will provide insight into general DNA repair processes that maintain genomic stability during antigen receptor diversification. We are also investigating how disruptions of that process lead to immunodeficiency, leukemias, and lymphomas.

Skolnik Lab

The insulin receptor (IR) is a tyrosine kinase receptor and induces a cellular response by phosphorylating proteins on their tyrosine residues. The IR is known to phosphorylate several proteins in the cytoplasm, including insulin receptor substrates (IRSs) and Shc. IRSs and Shc function as a docking protein for SH2-domain containing signaling molecules, which perform the next steps in the signaling cascade. Phosphatidylinositol 3-kinase (PKI3) is one signaling molecule that is activated by binding IRSs and is important in coupling the IR to glucose uptake. PKI3 mediates glucose uptake by the IR as well as a variety of other cellular responses by generating PI(3,4)P2 and PI(3,4,5)P3. PI(3,4)P2 and PI(3,4,5)P3 then function directly as second messengers to activate downstream signaling molecules by binding pleckstrin homology (PH) domains in these signaling molecules. To understand the molecular mechanisms whereby PI3-kinase couples the IR to glucose uptake and other cellular responses which include cell growth, inhibition of apoptosis, actin cytoskeletal reorganization, and protein trafficking, we have established a novel assay in the yeast S. cerevisiae to identify proteins that bind PI(3,4)P2 and PI(3,4,5)P3 in vivo. Using this assay, we have identified and cloned several new PI3K targets. Currently, we are working to elucidate the function of these proteins in PI3K signaling.

Smith Lab

The focus of our research is to understand the molecular basis of telomere function in human cells. Telomeres, the ends of chromosomes, consist of long tandem arrays of G-rich repeats bound to specific proteins. Telomeres act as protective caps and serve as templates for replication by the enzyme telomerase. Telomere integrity is essential for chromosome stability and maintenance, and telomeres play a key role in replicative senescence and cancer. To elucidate the molecular mechanisms that control telomere length and chromosome end protection we are investigating the protein components of the telomeric complex. Telomeres are coated by sequence-specific DNA binding proteins, TRF1 associated proteins, TIN2, Tankyrase1, and Rap1. We would like to understand how these proteins regulate access of telomeres to telomerase and how they protect chromosome ends from cellular DNA repair systems.

We have made a number of discoveries about the function of Tankyrase1, a member of the poly(ADP-ribose) polymerase (PARP) family of enzymes. We are currently taking a number of approaches to further investigate tankyrase 1, including RNA interference to knockdown expression in human tumor and primary cells and use of an in vitro PARP assay, to screen for activators or inhibitors of tankyrase1's PARP activity. We are also investigating the function and mechanism of two other TRF1-interacting proteins (Tankyrase2 and TIN2) that influence telomere length regulation.

Schwab Lab

The lipid sphingosine-1-phosphate (S1P) plays critical roles in the immune system and blood vessel development. S1P is an indispensable guidance cue for B and T cell migration, and has been suggested to act as an inflammatory stimulus in a range of settings. Furthermore, mice that cannot produce S1P die at mid-gestation due to a failure in vascular development, and S1P may promote angiogenesis in the adult. Despite the key roles of this signaling lipid in mammalian biology, we understand little about how its production and distribution are regulated. We are taking a variety of approaches to explore how S1P levels are set, and how S1P affects immunity.