Beatrix Bartok, MD
University of California
San Diego, CA
Rheumatoid arthritis is a chronic, debilitating condition that affects about 1% of the population in U.S. Chronic inflammation leads to joint destruction, loss of function, and severe disability in addition to shortened life expectancy, most commonly as a result of accelerated heart disease. Despite the major breakthrough with the introduction of biologics, treatment of rheumatoid arthritis remains an unmet medical need. These costly therapies have not been effective in all patients nor have they shown long lasting benefit after discontinuation.
Fibroblast-like synoviocytes are resident cells of the joints that play a critical role in rheumatoid arthritis by participating in inflammation and joint destruction in concert with the cells of the immune system. Therefore, therapies that specifically target these cells are highly desirable and have the potential to halt disease progression and even be curative. The proposal focuses on the investigation of a novel protein called YAP and signaling pathway that is dysregulated in rheumatoid arthritis and might be responsible for synoviocytes’ mediated joint destruction and inflammation. Reprogramming fibroblast-like synoviocytes by modulating the YAP pathway can lead to novel and effective therapy for patients with rheumatoid arthritis.
Scott Canna, MD
National Institutes of Health
Molecular Immunology and Inflammation Branch
Macrophage Activation Syndrome (MAS) is a life-threatening complication of a number of rheumatic illnesses, particularly systemic juvenile idiopathic arthritis. It manifests as the rapid onset of severe systemic inflammation. Currently, our understanding of the causes, risk factors, diagnosis, and treatment of MAS remains very poor. Initial investigations have implicated abnormal signaling through Toll-like Receptors (TLRs) or dysregulated function of the anti-inflammatory cytokine Interleukin 10.
Using clues from patients and model systems, Dr. Canna aims to understand how such defects contribute to MAS. Dr. Canna is the recipient of The Kelly Award for Juvenile Arthritis Research for 2013.
Denis Evseenko, PhD
University of California
Los Angeles, CA
Posttraumatic cartilage injury is one of the most significant problems among orthopaedic surgery patients. There is strong evidence that cartilage lesions predispose to osteoarthritis when left untreated. Osteoarthritis is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and bone. OA is the most common type of arthritis.
Different cell types have been studied with respect to their ability to generate articular cartilage. Unfortunately, cartilage tissue derived from these populations represents functionally inferior fibrocartilage, characterized by massive and disorganized collagen 1 deposition while normal hyaline articular cartilage predominantly contains collagen type 2. Dr. Evseenko’s study identifies a novel potential regulator – lysophoshatidic acid (LPA) — that can play a mechanistic role in the process of fibrocartilage formation.
The overall goal of this work is to determine if modulation of the LPA signaling can be used to direct stem cell differentiation, so that cartilage defects are repaired with hyaline articular cartilage rather than fibrocartilage preventing progression of osteoarthritis.
Stephen Gauld, PhD
Medical College of Wisconsin
Lupus is a chronic autoimmune disease driven by the production of autoantibodies. Our understanding of the mechanism(s) that drive autoantibody production in lupus remains poorly defined.
Dr Gauld’s research group has discovered that a population of cells, called regulatory T cells (or Tregs), is essential to prevent autoantibody production. Tregs stop autoantibody production by preventing the expansion of a new, highly novel population of cells, called TAN cells. The goal of this project is to understand more about TAN cells. In particular, Dr Gauld’s research will investigate how TAN cells develop and how they instruct other cells to make autoantibodies. Achieving these goals could help identify new therapeutic targets for the treatment of lupus.
Gonghua Huang, PhD
St. Jude Children’s Research Hospital
A more effective therapy for RA could be developed if the targeting of cells studied by Dr. Huang is successful. Rheumatoid arthritis (RA) and its mouse model, collagen-induced arthritis (CIA), are characterized by systemic and synovial tissue inflammation, beginning in the joints.
TH17 cells play a key role in the pathogenesis of arthritis. In this study, Dr. Huang examines the roles and mechanisms of p38α signaling in TH17 cell differentiation and function and the progression of collagen-induced arthritis in mice. His study may show that selectively targeting these cells would improve the efficiency of current treatments, and the use of novel drug-delivery vehicles to target the p38α inhibitors to specific tissue or cell types would be a promising strategy to avoid undesired side effects.
Andreia Ionescu, PhD
Harvard Medical School
Because FoxA transcription factors play an important role in skeletal development, Dr. Ionescu has begun to explore whether this transcription factor family also plays a role during conditions such as osteoarthritis. So far, she has found that over-expression of the gene, FoxA2, in a murine model of osteoarthritis accelerates progression of the disease while deletion of this gene in osteoarthritis prevents disease progression and protects against cartilage degradation in the joints.
This raises the interesting possibility that the induced expression of FoxA transcription factors during osteoarthritis leads to cartilage degradation. Thus, FoxA2 may be an interesting target for small-molecule inhibition in hopes of preventing OA.
Julia Jellusova, PhD
Sanford Burnham Medical Research Institute
La Jolla, CA
B cells are an important part of a normal immune system; however, their function is altered in patients suffering from many autoimmune diseases. Patients with rheumatoid arthritis have been shown to benefit from treatment targeting this cell population. BAFF is a crucial survival factor for B cells and BAFF serum levels have been shown to be elevated in patients suffering from different autoimmune disorders including rheumatoid arthritis. This project will study biochemical signaling pathways activated in B cells by BAFF and their contribution to B cell maturation and survival. A better understanding of these signaling pathways could lead to the development of new therapeutic agents or treatment strategies.
Nicole Joller, PhD
Brigham and Women’s Hospital
T cells that are activated by and react to the body’s own tissues are among the cells that drive autoimmune diseases such as rheumatoid arthritis (RA). Whether a T cell becomes fully activated is controlled by two mechanisms: 1) regulatory T cells inhibit T cell responses that are directed against the body’s own tissues and 2) so-called co-stimulatory and co-inhibitory molecules fine tune the T cell response and set the threshold for T cell activation. Among these, the co-inhibitory molecule TIGIT was recently linked to susceptibility to multiple autoimmune diseases, including RA. Dr. Joller’s study will determine how TIGIT regulates the autoimmune T cell responses that drive RA.
Dr. Joller will pursue an interdisciplinary approach to elucidate the inhibitory function of TIGIT. The knowledge gained through this approach will help Dr. Joller identify therapeutic targets and opens up different possibilities for the development of new therapeutic strategies.
George Kalliolias, MD, PhD
Hospital for Special Surgery
New York, NY
Rheumatoid arthritis (RA) is characterized by chronic unremitting joint inflammation. Despite the progress in our understanding of RA pathogenesis, sustained disease remission is an unmet need for >50% of RA patients. The goal of this project is to identify novel therapeutic targets to stop efficiently and safely the damaging progress of RA.
Dr. Kalliolias hypothesizes that the new targets to block are fibroblast-like synoviocytes (FLS), critical players helping perpetuate joint inflammation. Approved therapies for RA target immune cells or their products primarily and, to date, there is no therapeutic strategy available to block the disease-causing functions of FLS.
Dr. Kalliolias anticipates these studies will set the stage for designing novel FLS-targeting therapies, enriching the existing therapies available without increasing immuno-suppression of RA patients.
The Sontag Foundation felt that Dr. Kalliolias and his innovative project were among the most promising of this year’s RA-related projects and named him The Sontag Fellow of the Arthritis National Research Foundation for 2013-14. Learn more about The Sontag Foundation’s commitment to rheumatoid arthritis research at https://curearthritis.org/the-sontag-foundation/.
Lara Longobardi, PhD
University of North Carolina
Chapel Hill, NC
Osteoarthritis (OA) is the most common form of arthritis and current therapies primarily treat pain symptoms. The lack of a cure for OA clearly indicates that novel investigative approaches are needed to elucidate the functional changes occurring during this joint degenerative disease and to develop new therapies.
A joint is the location at which two or more bones connect and is surrounded by the joint capsule. The joint capsule is filled with a viscous fluid (synovial fluid) that protects the cartilage located at the surfaces of bones, called articular cartilage. In healthy joints, a proper joint structure is maintained by preventing the cells of the articular cartilage from undergoing mineralization followed by bone replacement, such as normally occurs during long bone growth.
If OA is the result of the failure of articular cells to establish the correct microenvironment and prevent joint mineralization, understanding the mechanism by which these cells preserve articular cartilage in adults can lead to understand how cartilage is damaged and to develop new treatments for OA.
Dr. Longobardi’s study is based on her original finding that the growth factor TGF-β (Transforming Growth factor-β), which is known to have a critical role in preserving the joint structure, can modulate joint development during fetal life by selectively repressing specific molecules secreted by inflammatory cells (cytokines), such as MCP-5 (Monocyte Chemoattractant protein-5). It has been proved that a correct balance between growth factors and cytokines is critical to maintain the properties of the articular cartilage.
The overall objective of the proposal is to analyze in more detail the mechanism by which TGF-β and MCP-5 interact and the molecules they activate to preserve joint integrity. This is a novel perspective to study OA disease progression in which joints are not the passive “victims” of the degenerative force of inflammation but rather make their own contribution to OA pathogenesis by the failure of an active cell joint population to maintain a controlled environment. The information derived from these studies has major medical relevance and implications as it will provide critical insights to the chain of events that lead to OA pointing the research toward novel therapies to restore joint function.
Subbarao Malireddi, PhD
St. Jude Children’s Hospital
Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects joints leading to joint pain, stiffness, deformity and disability. Collagen induced arthritis (CIA) is a classic mouse model of RA which has substantially furthered our knowledge about the mechanism of the disease. Although RA is traditionally known as an autoimmune disease, innate immunity orchestrates the development of adaptive responses and pathogenic responses that drive RA. Targeting innate immune responses has proven beneficial in RA patients. Nucleotide binding and Oligomerization Domain (NOD)-like Receptors (NLRs) have recently emerged as important regulators of the innate immune response.
In this study, Dr. Malireddi will evaluate the role of NOD like receptor protein NLRP12 in the negative regulation of the immune response in rheumatoid arthritis using the CIA mouse model. This study could reveal the essential mechanisms of the innate immune responses required for suppressing inflammation and subsequently controlling arthritis causing factors. An understanding of such anti-inflammatory mechanism is a prerequisite for the development of new therapies.
Laurent Reber, Ph.D.
Gout and pseudogout are chronic diseases caused by the precipitation in the joints of crystals of monosodium urate and calcium pyrophosphate dihydrate. Defining which cell types in the affected joints initiate and/or perpetuate the inflammatory response and related joint pathology induced by such crystals is an essential step towards finding more effective treatments.
Mast cells are potent pro-inflammatory immune cells which are abundant in the joints but their role in gout and pseudogout remains unknown. In this project, Dr. Reber will define mechanisms by which mast cells contribute to joint disease in mouse models of gout and pseudogout and assess whether and to what extent targeted inhibition of mast cell functions can reduce inflammation and disease pathology.
Junxia Wang, PhD
Harvard Medical School
The neutrophil represents the front line of immune defense, migrating first into inflamed tissues to clear invading pathogens. However, in rheumatoid arthritis (RA) and other types of arthritis, neutrophil recruitment into the joints continues unabated for years, contributing to pain, joint swelling, and tissue destruction. Animal studies demonstrate that neutrophils serve a lynchpin role in both initiation and perpetuation of joint inflammation. Therefore, neutrophils are a potentially interesting therapeutic target.
The project will pursue the discovery of a novel regulator of human neutrophil migration, to understand how it works and to determine whether this protein could serve as a therapeutic target in inflammatory diseases such as arthritis.
Hong Zan, PhD
University of California
Systemic lupus erythematosus (lupus) is an autoimmune disease characterized by the production of an array of pathogenic autoantibodies (antibodies that attack self tissues), which cause widespread tissue and organ injury.
Both genetic factors and epigenetic modifications that arise from exposure to the environment contribute to the pathogenesis of lupus. The word “epigenetic” literally means “in addition to changes in genetic sequence.” The term has evolved to include any process that alters gene activity without changing the DNA sequence, and leads to modifications that can be transmitted to daughter cells.
Dr. Zan’s research addresses core autoimmune mechanisms of lupus and will have sustained impact on the fields of epigenetics, immunoregulation and autoimmunity. This study will provide a sound mechanistic basis for use of inexpensive small molecule epigenetic inhibitors, some of which are already available and FDA-approved, to treat lupus more effectively.
Mara McAdams DeMarco, PhD
Johns Hopkins University
Gout is the most common form of inflammatory arthritis and disproportionately affects adults over the age of 65; an estimated 4.7 million older adults have been diagnosed with gout in the US. There is increasing awareness that the risk factors, clinical presentation, and progression of gout differs for older adults.
To address the growing public health burden and distinct clinical aspects of gout in older adults, Dr. McAdams DeMarco’s research will estimate the number of older adults who develop gout, identify risk factors for gout in older adults, and determine the impact of gout on physical function in older adults. The findings from this research will lead to a better understanding of the burden, risk factors, and consequences of gout in older adults and will directly benefit patients and providers by characterizing this inflammatory arthritis in an understudied population.
Dr. McAdams DeMarco’s research is co-funded by ANRF and the American Federation for Aging Research (AFAR).