PGP 2008-2009 | PGP 2009-2010 | PGP 2010-2011
SRP 2009-2010 | SRP 2010-2011
DAP: 2008 | 2009 | 2010 | 2011
PPG: 2008 | 2009 | 2010
SRI in OA 2003-2008 | SRI in IJD 2006-2011 | SRI in BIO 2008-2012
SRID: 2007-2008 | 2006-2007 | 2005-2006 | 2004-2005 | 2003-2005 | 2002-2004

Research Grants Awards

Research funding: 2008

DAP 2008

The Nerve of Osteoarthritis Pain

Gillian Hawker, Women's College Hospital

Abstract: The proposed study aims to address current gaps in our understanding of what causes pain in OA. In particular, we plan to assess signs and symptoms of hyperactivity along the pain transmission pathways, called pain sensitization or neuropathic pain. A two-phase study will be conducted in an existing cohort of people, aged 65+ years, with OA. Phase I will evaluate the distribution of symptom scores on a modified neuropathic pain questionnaire (the mPD-Q, which has been modified to improve its suitability for use in older people with knee OA) and assess questionnaire validity through comparison with responses on other commonly used pain questionnaires. In Phase II, we will evaluate 1. the pattern of sensory abnormalities in people with painful knee OA compared to controls using quantitative sensory testing (QST), 2. the relationship between self-reported symptoms (using the mPD-Q) and sensory abnormalities (using QST), and 3. whether symptom scores could be used to identify people who are likely to have sensory abnormalities suggesting pain sensitization on examination.

Cross-cultural adaptation of an early inflammatory arthritis screening tool

Mary Bell, Sunnybrook Health Sciences Centre

Abstract: A patient, self-administered questionnaire has been developed that may be able to identify inflammatory arthritis at the offices of family doctors. Patients identified with inflammatory arthritis from this questionnaire can then be referred directly to an arthritis specialist. This questionnaire has been developed in English and is currently being tested across Canada to prove these claims. A small study including 205 patients from the offices of family doctors was completed using this questionnaire and the results look promising. A larger study is currently being conducted with the English tool to better determine how well it can identify inflammatory arthritis patients from the offices of family doctors. One of the limitations of this questionnaire is that it is currently only available in English. The purpose of this study is to translate it into French in such a way that the expressions in the translated document have the equivalent meaning as in the original English version. Other researchers have previously shown that the direct translation of tools similar to this one may not have the same meaning once they have been translated. Therefore, this study aims to use an accepted scientific approach to creating for the Canadian French culture, a questionnaire that is equivalent to the existing English version. The second part of the study is to then prove that the French questionnaire is equivalent to the English version.

Effect of autotaxin inhibitors with potent antagonistic activity at LPA receptors on collagen-induced arthritis

Sylvain Bourgoin, Universite Laval

Abstract: We recently demonstrated that autotaxin (ATX), which is the dominant source of extracellular LPA, is present at high levels in synovial fluids from rheumatoid arthritis patients. In inflammatory synoviocytes, the expression of cytokine/chemokine genes is super-induced by LPA via activation of specific LPA receptors. We believe that ATX and LPA receptors represent attractive new therapeutic targets for the control of inflammation associated with arthritis. We intend to demonstrate this novel idea in a mouse model of arthritis. In this research project, we describe experiments aimed at investigating the effect of a potent inhibitor of ATX and antagonist of LPA receptors in reducing the inflammation in a model of arthritis.

Contribution of CD154 binding to its receptors to the development of Rheumatoid Arthritis

Walid Mourad, CHUM

Abstract: Rheumatoid arthritis (RA) is an inflammatory disease, where several cell types are actively involved in joint destruction through their production of various inflammatory mediators. Among the proteins that are known to play a key role in these interactions are the CD154 molecule and its receptors. Abolishing the interaction of CD154 with its receptors would certainly affect the clinical manifestation of RA. Our group generated CD154 mutant proteins that are able to specifically bind to and block one receptor of CD154 without the others. In the current proposal, we will use these CD154 mutations in genetically modified mice, termed knockin mice. These mice will be further induced to develop RA. Data generated from these studies will provide us with the pre-clinical evidence needed to prove the efficiency of our CD154 mutants in treatment of inflammatory diseases such as RA.

Stimulating chondrogenesis through manipulation of intracellular signaling pathways

Frank Beier, University of Western Ontario

Abstract: One important avenue of arthritis research is to improve on whole joint replacement techniques with tissue engineered cartilage, or engineered whole/partial joints. We identified several drugs that can promote cartilage generation from precursor cells. We now propose to optimize combinations of these drugs to stimulate human mesenchymal stem cells isolated from bone marrow to become cartilage in tissue culture. These drugs show much promise and have not been implicated previously as potential therapeutics for cartilage formation. From work we have already completed in models, we hypothesize that we will be able to promote bone marrow stem cells to become fully functional cartilage cells. We propose to determine the optimal dose, length of treatment and possible combination of compounds in order to generate the most functional cartilage tissue explant, for subsequent use in joint replacement. Our proposal is unique in that the compounds we propose to use are much more cost effective than the existing growth factors that are utilized in current approaches. Because cost is always an issue, if we can promote cartilage formation more effectively at a fraction of the price, the use of engineered cartilage will be more feasible for use as a therapeutic in the near future.

Preclinical testing of human monoclonal antibodies that neutralize the pro-inflammatory arthritogenic cytokine GM-CSF

John Schrader, University of British Columbia

Abstract: We have used new techniques to make truly human monoclonal antibodies that neutralize GM-CSF, a protein that causes inflammation and arthritis. The research will demonstrate that our antibodies to GM-CSF block its ability to activate human white blood cells to make TNF and enzymes that destroy joints. The research will also test the novel idea that the injection of two carefully chosen antibodies against GM-CSF will be much more effective in blockading GM-CSF.

The evaluation of a novel therapeutic target for rheumatoid arthritis

Maria Fernandes

Abstract: We recently made a novel and exciting observation in the synovium of individuals with rheumatoid arthritis. We observed the presence of a protein in the newly-formed blood vessels. This protein is called angiomotin and is known to induce the formation of new blood vessels. The formation of new blood vessels in rheumatoid arthritis increases the blood supply to the synovium, exacerbates the inflammatory reaction and favors the progression of the disease. By inhibiting the formation of new blood vessels, the symptoms and progression of rheumatoid arthritis could be significantly ameliorated. Blocking blood vessels formation has already provided encouraging results in animal models of arthritis. We propose to develop a similar approach by blocking the activity of angiomotin.

Development of a novel target for high throughput antiresorptive drug screening

Morrie Manolson

Abstract: Healthy bone is continuously dissolved and replaced in a life-long process called remodeling. Specialized cells called osteoclasts use acid to dissolve tiny pits in bone, which are then filled in by a second cell type. Osteoclasts use a protein "acid pump," or "V-ATPase," to secrete acid for bone resorption.

Too much acid pump activity leads to disease. In osteoporosis and inflammatory arthritis, there is too much bone resorption, resulting in fragile bone and collapse of joint surfaces. It would be of value to be able to turn off the acid pump; however, a variety of other essential functions in all tissues require very similar acid pumps. Our goal is to stop the osteoclast acid pump responsible for bone loss, without affecting acid pumps needed for other essential tasks.

My lab has discovered unique characteristics of the V-ATPase in osteoclasts that distinguish it from V-ATPases in other cells. Furthermore, we have found ways to model these unique characteristics in the laboratory. In this application, we propose to use the laboratory model to rapidly screen for chemical compounds that inhibit osteoclast activity specifically. These compounds will then be tested for their ability to prevent bone loss. In the long term, one of these compounds may be developed into a new drug with greater benefits for restoring bone and preventing bone loss, and fewer harmful side effects.

I personally have been diagnosed with psoriatic arthritis, but I am unwilling to take available therapeutics (bisphosphonates and immunosuppressants) because of their side effects. Nevertheless, if untreated, I will lose mobility in my wrists and back. A therapeutic to stop bone loss in arthritis, without serious side effects, would be a very welcome advancement.

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