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Research

The laboratory studies the mechanisms of action of signaling molecules encoded by human disease-predisposing genes and analyzes signal transduction pathways in pathological specimens from patients. Our goal is to dissect relevant intracellular pathways to design new methods for disease activity monitoring and to identify new treatment strategies.

The laboratory specializes in the study of a family of signaling enzymes called protein tyrosine phosphatases that regulate phosphorylation of proteins on tyrosine residues.

We emphasize translational "bed to bench to bedside" research. Collaborations with pharmaceutical companies are routinely sought to accelerate translation of laboratory findings into the clinic.
 
FUNCTIONAL GENETICS OF AUTOIMMUNE DISEASES

WHY
 we work in this area
Autoimmune diseases are caused by a complex combination of genetic and environmental factors. Genetic studies have identified many autoimmunity genes, but the mechanisms of action of most of these genes in human autoimmunity is currently unknown. Understanding the effects of disease-associated genetic variations on gene function is important because it might pave the way to targeting these genes or other components of the pathways to which the genes belong for novel therapies. In addition, genes are partially responsible for the fact that not all therapies work in all patients. Thus, studying the function of such genes will enable development of more efficient personalized therapies that are tailored on the specific mechanism that causes disease in each patient.

WHAT we are doing in this area
Two major autoimmunity genes, PTPN22 and PTPN2 encode for enzymes with tyrosine phosphatase activity. Dr. Bottini reported the initial discovery that a single nucleotide substitution in PTPN22 significantly increases the risk of autoimmunity in human carriers. PTPN22 currently ranks as the second most important gene in rheumatoid arthritis and the third in type 1 diabetes. It also increases the risk of systemic lupus erythematosus, systemic sclerosis and other autoimmune diseases. To understand the mechanism of action of PTPN2 and PTPN22 in autoimmunity, we use a range of approaches from manipulation of PTPN22 expression in cells from human subjects, to modeling of the gene function in mice affected by autoimmune disease.

HOW we support our work in this area
Our work on the functional genetics of autoimmune diseases is supported by the NIAID.

MOST RECENT PUBLICATIONS from our laboratory in this area
https://www.jci.org/articles/view/123267 By modeling the effect of loss of function variants of PTPN2 in mouse models of rheumatoid arthritis, we have identified a role for PTPN2 in maintenance of regulatory T cell stability in the context of inflammation.
https://www.ncbi.nlm.nih.gov/pubmed/32184287 We have identified a mechanism of biochemical regulation of PTPN22 in T cells that controls both PTPN22 half-life and its recruitment to the plasma membrane during signaling.
 
RHEUMATOID SYNOVIOCYTES

WHY we work in this area
Rheumatoid arthritis is the most common systemic autoimmune disease. In rheumatoid arthritis, the immune system mistakenly attacks joint tissues, causing inflammation. If the inflammation is not controlled, with time it leads to damage of joint cartilage and bone, resulting in deformities of the joints, chronic pain and functional limitations. Immunological research has led to the development of several rheumatoid arthritis medications able to suppress the hyperactivation of the immune system (so called immunosuppressants). Although immunosuppressants are in general very effective, a consistent proportion of patients (up to 1/3) do not experience a complete remission of their symptoms, despite trying several of these medications. Further suppression of the immune system in these patients would increase the risk of infections to unacceptable levels. Therefore, our goal is to explore other therapies that can be used in combination with immunosuppressants in hopes to benefit rheumatoid arthritis patients who do not respond well to immunosuppressants alone.

WHAT we are doing in this area
We turned our attention to a cell type that is present locally in the joint lining, called the synoviocyte. Synoviocytes are sensitive to the activation of cells of the immune system in the joints and in rheumatoid arthritis play a disease-promoting role by boosting inflammation, directly damaging the cartilage, and indirectly stimulating the cells that damage the bone. Inhibition of synoviocyte activity is believed to result in decreased inflammation and joint damage but it does not result in general suppression of the immune system. Thus, anti-synoviocyte therapies could be combined with currently available immunosuppressive therapies to improve control of disease activity in subjects who do not respond well to the immunosuppressant alone. We study biochemical signaling pathways inside synoviocytes trying to identify pathways that are abnormal in RA and/or can be targeted to reduce the activation of synoviocytes in RA. We found that synoviocytes express several molecules with tyrosine phosphatase activity and we are now focused on studying these molecules and assessing whether they can be targeted for therapies for RA.

HOW we support our work in this area
Our work on synoviocytes is supported by the NIAMS, and a contract from industry.

MOST RECENT PUBLICATIONS from our laboratory in this area
https://www.ncbi.nlm.nih.gov/pubmed/30808624 We report that through the regulation of TGFbeta signaling and activation of the YAP pathway, the tyrosine phosphatase PTPN14 promotes the pathogenic action of synoviocytes in rheumatoid arthritis patients.
https://www.ncbi.nlm.nih.gov/pubmed/27275015 We describe abnormal epigenetic regulation of the PTPN11 gene –encoding the tyrosine phosphatase SHP-2- in synoviocytes from rheumatoid arthritis patients, and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for rheumatoid arthritis.
https://www.ncbi.nlm.nih.gov/pubmed/26414708 We found that through regulation of SRC and FAK phosphorylation, the receptor tyrosine phosphatase RPTPα mediates pro-invasive signaling in synoviocytes from rheumatoid arthritis patients, which promotes disease in a synoviocyte-dependent model of rheumatoid arthritis.
 
SYSTEMIC SCLEROSIS AND ORGAN FIBROSIS

WHY we work in this area
Systemic sclerosis is an autoimmune disease that leads to scarring of the skin and internal organs (called “fibrosis”), resulting in significant limitations in quality of life and often reduced life expectancy in patients. Most patients are diagnosed at a stage of disease when some fibrosis of the skin and the internal organs has already occurred. In that stage, steroids and immunosuppression are ineffective at slowing down the scarring. There is a critical need for medications that can significantly reduce progression of fibrosis in systemic sclerosis and other fibrotic diseases (such as idiopathic pulmonary fibrosis, liver fibrosis, and cardiac fibrosis). A cell type that promotes fibrosis in all these diseases is the fibroblast. Fibroblasts are normally responsible for wound healing, however in fibrotic diseases they become abnormally hyperactive and produce increased amounts of tissue matrix, leading to inappropriate scarring. Targeting fibroblast signaling or the cells and pathways that lead to fibroblast stimulation could modify disease course in systemic sclerosis and other fibrotic diseases.

WHAT we are doing in this area
We study biochemical signaling pathways inside fibroblasts and other cells, trying to identify pathways that are abnormal during fibrosis and/or can be targeted to reduce the abnormal tendency of fibroblasts to cause scarring. In preliminary experiments, we found that fibroblasts express several tyrosine phosphatases and we are now focused on studying these molecules and assessing whether they can be targeted for novel anti-fibrotic therapies. 

HOW we support our work in this area
Our work on systemic sclerosis and fibrosis is supported by the NHLBI.

MOST RECENT PUBLICATIONS from our laboratory in this area
https://www.nature.com/articles/s41467-017-01168-1 We report that the phosphatase PTP4A1 is overexpressed in systemic sclerosis fibroblasts and promotes pro-fibrotic TGFbeta signaling via enhancement of the half-life of the kinase SRC.