All grant applications are carefully reviewed by ANRF’s world-renowned Scientific Advisory Board of physician-scientists. The best and brightest emerging researchers with the most promising projects rise to the top. Only 15% of applicants received a grant this year.
This support helps launch these researchers on their independent research careers. They work in top laboratories and this funding enables them to make discoveries more quickly than without the extra support. And, time is important to those suffering with arthritis.
Below are this year’s researchers and a brief summary of their work:
Beatrix Bartok, MD
University of California
San Diego, CA
Damage in joints of patients with rheumatoid arthritis (RA) is induced by the patient’s immune system attacking its own joint tissues. However, a portion of this damage is caused by “resident” normal cells in the joint that have become altered during and after the immune attack. The altered resident cells undergo abnormal growth and healing which results in scarring, disfigurement and joint immobilization.
Studying joint tissue from human RA patients and mice, Dr. Bartok has discovered how the normal joint cells become altered by the immune attack. Her important findings can lead to the development of new methods to block this destructive cellular response. This can lead to new drugs and treatments to prevent and stop the progressive destruction of joint tissues in RA patients.
Dr. Bartok is this year’s John Vaughan Scholar as her work most closely aligns with that of Dr. Vaughan. Read more about Dr. Vaughan.
Pallavi Bhattaram, PhD
Rheumatoid arthritis is a common joint disease causing distress and disability in the affected individuals. Abnormal changes in specialized cells lining the joint surfaces, known as the fibroblasts-like synoviocytes, are one of the major causes of this disease. In healthy joints fibroblasts-like synoviocytes are critical for the maintenance of joint integrity. They produce molecules that lubricate joints and help to protect joints from wear and tear. However, in rheumatoid arthritis, these specialized cells transform into cancer-like cells. They increase in numbers and act as a source of molecules that destroy the joints.
Despite this knowledge, incomplete understanding of the genes and pathways that regulate fibroblasts-like synoviocytes has limited the development of treatment strategies that can target these cells. This study focuses on uncovering the roles of a group of genes that belong to the SOX family, in transforming the healthy joint protecting cells into joint destroying cells. The signaling pathways that are under the control of these SOX genes could be targeted to treat and limit the joint damage in rheumatoid arthritis.
Nidhi Bhutani, PhD
Osteoarthritis is the most common form of arthritis that affects approximately 27 million people in U.S. alone. Current treatments are however limited to pain management mainly because of a lack of understanding of the initiation and early stages of the disease. No disease-modifying OA drug is available as a result. OA is marked by joint dysfunction and particularly cartilage degeneration caused by the native cartilage cells themselves. Dr. Bhutani’s recent studies have identified that normal and OA cartilage cells from patients differ greatly in the function of a novel family of enzymes. These enzymes are responsible for modifying the DNA and such ‘epigenetic’ modifications affect widespread gene expression; therefore, these enzymes can be central regulators of the gene expression changes in OA.
Dr. Bhutani’s research will identify the genes that are regulated by these particular enzymes in OA cartilage to understand how they affect the initiation and progression of OA. Using mice that lack these enzymes, she will test how the absence of this regulator will modulate OA. Lastly, Dr. Bhutani will evaluate whether a pharmacological manipulation of these enzymes (and its targets) has the potential to be therapeutic in OA.
Dr. Bhutani is the ANRF-AFAR Grant Recipient – a special grant on aging co-funded by ANRF and the American Federation for Aging Research.
Susan Carpenter, PhD
University of California, San Francisco
While acute inflammation is mostly beneficial, unchecked or dysregulated inflammation can have devastating consequences leading to a wide range of diseases including Rheumatoid Arthritis, Systemic Lupus Erythematous, and Cancer. Thus, given the significance of these devastating diseases, new approaches towards understanding pathology and gene mechanism are urgently needed.
It has been over a decade since the human genome was sequenced. Since then, there have been huge improvements in our ability to carry out sequencing. The classical understanding of the genome was that DNA is transcribed into RNA, which makes proteins that carry out various biological functions. However, sequencing studies have shown that only a small portion (2%) of the genome results in protein, yet there are very large amounts of RNA being produced (85% of the genome). The major class of RNA molecules produced from the genome are called long noncoding RNA (lncRNA). These RNA molecules are emerging as fundamental mediators of innate immune signaling pathways.
Dr. Carpenter’s research has identified lincRNA-Cox2 as a highly inducible gene in response to inflammatory stimuli and functions to repress interferon stimulated gene (ISG) expression while also being required for the induction of other inflammatory genes such as IL-6. She has identified functional interactions between lincRNA-Cox2 and the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP-A2/B1), also known as RA33, an auto-antigen in rheumatoid arthritis.
This project aims to understand how lincRNA-Cox2 and RA33 are involved in the pathogenesis of inflammatory arthritis. Obtaining a better understanding of the role of these RNA molecules in inflammatory conditions could lead to the development of new biomarkers for disease and unveil new therapeutic targets.
Denis Evseenko, MD, PhD
University of California, Los Angeles
Articular cartilage is a type of connective tissue that covers the surfaces of bones within synovial joints. Articular cartilage injury and the lack of cartilage regeneration often lead to osteoarthritis. Recent studies carried out by Dr. Evseenko and his lab and others have shown that stem/progenitor cells can partially repair damage cartilage, but more work is needed to increase the efficiency of this therapy. Unfortunately, limited survival and degeneration of implanted stem/progenitor cells, as well as excessive collagen type I (COL I) deposition leading to formation of mechanically inferior tissue, are the standard outcomes of currently used cell-based cartilage restoration techniques.
Dr. Evseenko proposes a novel approach based on his recent findings and the development of an essential model to test this and subsequent therapeutic methods. He will use a highly purified population of cartilage stem cells identified in his lab’s recent studies of normal human cartilage development. His team will also manipulate signaling driven by the small biogenic lipid LPA, having recently shown that LPA is highly expressed in the site of cartilage injury driving COL I deposition, which in turn leads to fibrosis and limits the expansion and survival of implanted stem cells. In rat studies, his team has also shown that pharmacological inhibition of the LPA-signaling reduces fibrosis and results in enhanced production of neocartilage at the site of injury.
During this second year of ANRF support, Dr. Evseenko will access this novel approach in a large animal model of joint injury and apply a highly innovative robotic approach to assess the biomechanical properties of repaired joints, in addition to the routine histological tests. The ultimate objective of the proposed project is to develop new therapeutic approaches for articular cartilage restoration, which in turn will reduce the morbidity from acute cartilage injuries and degenerative joint disease.
Dr. Evseenko is this year’s James Klinenberg Scholar as his work at UCLA closely aligns with that of Dr. Klinenberg. Read more about Dr. Klinenberg.
J. Michelle Kahlenberg, MD, PhD
University of Michigan
Systemic lupus erythematosus (SLE or lupus) is a severe autoimmune disorder that can adversely affect many organs, including the skin, kidney, blood and joints. This organ damage can result in substantial morbidity or even death. In patients suffering from lupus, their disease course is characterized by “flares” of increased disease activity that require treatment with aggressive immunosuppressive medications. Often, these flares can be heralded by the presence of a lupus rash. However, how this rash relates to systemic disease development remains unclear.
In most murine models of lupus, the onset of disease is a gradual process, and it has been difficult to model how a flare occurs. In her work, Dr. Kahlenberg has developed a model in which lupus-prone female mice develop a rapid flare of kidney disease following skin injury. This project proposes to determine the mechanisms by which skin injury can lead to a rapid flare of kidney inflammation in these mice. She will investigate this by undertaking a systematic exploration of the inflammatory cell populations present in the kidney and relate this to simultaneous changes in the skin and blood of the mice. Additionally, she and her team will target the cytokine IL-18 to determine whether induction of flares of kidney inflammation by skin injury requires this cytokine.
She anticipates this work will show that skin injury rapidly increases the inflammatory cell populations in the kidney and that blocking IL-18 may modulate this. This work will benefit the scientific community by increasing knowledge of how the skin and kidney may cross-talk in lupus, thus leading to development of novel therapies that may help to prevent flares of lupus nephritis and reduce the need for immunosuppressive medications in lupus patients.
Dr. Evseenko is this year’s Eng Tan Scholar as her work most closely aligns with that of Dr. Tan. Read more about Dr. Tan.
George Kalliolias, MD, PhD
Hospital for Special Surgery
New York, NY
Rheumatoid arthritis (RA) affects 0.5-1% of the general population and is characterized by joint inflammation (arthritis) and increased mortality, primarily due to heart attack and stroke. Scientific breakthroughs during the last 20 years have enriched our therapeutic “medicine chest” with biologic therapies and kinase inhibitors, leading to a dramatic improvement in patients’ quality of life. Despite this progress there are still unmet needs including the low rates of sustained disease remission and the inadequate response to therapy in about 1/3 of RA patients. In this context, it is necessary to implement more individualized treatment protocols and identify safer and more effective therapies. The path to achieve these goals is to understand in depth the molecular events implicated in RA pathogensis.
Dr. Kalliolias uses novel technologies to characterize the role of synovial fibroblasts (SF) in RA pathogenesis. SF are resident cells of the normal joint that become activated in RA. Although their implication in the inflammatory and destructive processes of RA has been considered for a long time, none of the existing therapies for RA targets SF. HIs previous studies have shown that SF display an uncontrolled inflammatory response to factors found in abundance within the inflamed joint of RA patients. These findings led to the hypothesis that SF of RA patients lack the appropriate “brakes” that should turn off inflammatory responses. Currently, Dr. Kalliolias is testing this hypothesis with an ultimate goal to identify strategies to terminate or block the production of inflammatory and tissue destructive mediators by SF. His long-term goal is to set the stage for the development of drugs for RA patients that will target SF, supplementing the existing therapies that target the immune system.
Dr. Kalliolias was named the first Gale A. Granger Scholar, as his work most closely aligned with that of Dr. Granger, former ANRF grant recipient and board member who initially discovered tumor necrosis factor (TNF) and its receptors. Click here to watch an interview with Dr. Granger.
Martin Kriegel, MD, PhD
New Haven, CT
Antiphospholipid syndrome (APS) is a serious autoimmune clotting disorder in which the immune system mistakenly attacks a self-protein in the blood. The “auto antibodies” that attack self molecules in blood are found in certain patients with rheumatoid arthritis, lupus and other autoimmune diseases. When the auto antibodies react with self molecules they form clots in the blood stream that can lodge in tissues causing stroke, heart attack and death. What induces the patient’s immune system to react against these self molecules is not known.
Dr. Kriegel has found that certain bacteria living in the digestive tract of patients with APS trick the immune system to react against the self molecules. These are important findings for they reveal 1) how this disease starts which may serve as a model of how other types of autoimmune disease can start and, 2) how to diagnose, prevent and stop the progression of this particular disease.
Dipak Patel, MD, PhD
University of Michigan
Ann Arbor, MI
Nutrition can have a profound effect on disease development. Most current studies have focused on how macro-nutrition (calorie, carbohydrate, fat, and protein) affects diseases, but very little is known about the role that early life micro-nutrition plays in diseases such as rheumatoid arthritis (RA). Micronutrients such as folic acid and methionine produce methyl donors that can attach to DNA. The amount of protein produced by a gene can be increased or decreased by the amount of methyl donors attached to that gene’s DNA. When this happens, the gene is considered “methylation sensitive.”
Tissue damage in rheumatoid arthritis is caused by certain pro-inflammatory genes, and many of these genes are methylation sensitive. A subset of white blood cells, CD4+ T cells, contributes to RA by producing high levels of many pro-inflammatory proteins, and disease severity can be adjusted by controlling the methylation level of several of these genes. Feeding mice a diet rich in methyl donors during pregnancy affects expression of many of these genes in CD4+ T cells in their offspring mice (F1 methyl supplemented), compared to the offspring of pregnant mice that were fed a regular diet (F1 control). Genes favoring inflammation are expressed at lower levels in F1 methyl supplemented mice and, in a model of atherosclerosis (heart disease), F1 methyl supplemented mice had less severe disease than F1 control mice.
Dr. Patel predicts F1 methyl supplemented mice will have less severe rheumatoid arthritis, compared to F1 control mice, as well. His team has shown, in the collagen induced arthritis model, F1 methyl supplemented mice have decreased paw swelling compared to F1 control mice. To explain this, he expects that CD4+ T cells will express lower levels of pro-inflammatory mediators, and higher levels of anti-inflammatory mediators, in F1 methyl supplemented mice compared to F1 control mice.
These results have the potential to transform our understanding of how genes and the environment interact in RA and other chronic inflammatory diseases, and to identify a new paradigm in understanding and potentially treating inflammation and disease with pre-natal nutrition.
Junxia Wang, MD, PhD
Brigham & Women’s Hospital
Neutrophils are white blood cells which are important for the body’s defense against infectious agents. However, these same cells enter the joint in rheumatoid arthritis in large numbers and over time cause swelling, pain and tissue damage.
Dr. Wang has identified the mechanism of how neutrophils leave the blood stream and migrate into joint tissues. These are important findings for blocking the migration of neutrophils into the joint can prevent the onset of the disease and stop tissue damage. These results can lead to new methods to prevent and control RA and other forms of inflammatory arthritis.
Wentian Yang, MD, PhD
Brown University Medical School, Rhode Island Hospital
Current osteoarthritis (OA) treatment focuses on symptom relief but does not materially alter disease progression. OA prevention and treatment continue to be a clinical challenge due to the limited self-healing capacity of joint cartilage. Searching for cell sources capable of being mobilized and providing functional descendants in joint cartilage is of paramount importance to osteoarthritis prevention and treatment.
Dr. Yang and his team recently identified a population of cartilage progenitors/stem cells that express an enzyme called cathepsin K in joints; these cells are capable of forming cartilage and this function is enhanced in the absence of a certain protein, tyrosine phosphatase SHP2. The goal of this study is to further understand the role of this population of stem cells in joint cartilage development and homeostasis and the molecular mechanism through which this protein modulates the capability of the stem cells to form cartilage. Dr. Yang’s long-term objective is to develop strategies to inhibit cartilage degeneration and promote its regeneration by mobilizing this population of stem cells and/or modifying SHP2-regulated signaling pathway(s).
Hong Zan, PhD
University of Texas Health Science Center
San Antonio, TX
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease in which the immune system turns against parts of the body it is designed to protect. With lupus, instead of producing protective antibodies, the immune system makes autoantibodies, which attack the patient’s own tissues and cause widespread tissue and organ injury. These autoantibodies are secreted by large number of plasma cells, which are differentiated from a type of leukocytes (white blood cells) called B cells, and are heavily mutated on the antigen-binding domain and class-switched to mainly IgG isotype.
The pathogenesis of autoimmune diseases, including lupus, can be traced to both genetic elements and epigenetic modifications arising from exposure to the environment. Epigenetics involves genetic control by factors other than an individual’s own DNA sequence. Epigenetic factors, such as DNA methylation, histone modifications and microRNAs, can switch genes on or off and determine which proteins impact cell function. Like many other autoimmune diseases, lupus preferentially affects women during their reproductive years, suggesting that the female hormone estrogen, which promotes autoantibody response, plays an important role in causing lupus.
In Dr. Zan’s study, he and his team utilizes FDA-approved and widely-used epigenetic modulators to selectively inhibit the generation of pathogenic autoantibodies to prevent, treat or even cure lupus. With the second year support from Arthritis National Research Foundation, he will develop therapeutic approaches including combined treatment that target both estrogen receptor, which is important for effects of estrogen, and epigenetic factors, or target multiple epigenetic factors to synergistically dampen autoantibody responses, thereby, treat lupus more effectively. He will also attempt to gain further insight into B cell-intrinsic epigenetic mechanisms in the pathogenic lupus autoantibody response, and to unveil modulation of the epigenetic factors by estrogen.