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FOR IMMEDIATE RELEASE Arthritis National Research Foundation Long Beach, CA – Arthritis National Research Foundation (ANRF) grant recipients are highly qualified researchers with several years of post-doctoral experience, hoping that this grant award will help them launch their independent research careers. The ANRF is delighted to provide the funding they need at a pivotal time in their careers: they are affiliated with established laboratories at non-profit research universities or facilities and their projects show a great deal of promise to increase our understanding of arthritis diseases and developing new treatments. The following 14 researchers have been funded for the 2005-06 grant award period: New Therapeutic Target for Lupus Systemic lupus erythematosus (SLE or lupus) is a devastating chronic
autoimmune disease affecting multiple organ systems and characterized
by a broad array of antibodies. Dr. David Cauvi’s laboratory
has identified that a protein called decay accelerating factor (DAF),
is increased in lupus-resistant mice. Dr. Cauvi will test whether
an elevated level of DAF reduces the development of SLE by treating
lupus-prone mice with a soluble form of DAF. These experiments will
allow Dr. Cauvi to conclude whether or not DAF exerts a protective
role in the development of SLE, providing a new target for therapeutic
intervention, not only for SLE but for other autoimmune diseases,
as well. T lymphocytes, a type of white blood cell, play a central role in the regulation of immune responses against infection. The function of T lymphocytes is critically dependent upon their ability to distinguish between self and non-self. The inappropriate recognition of self tissues by T lymphocytes leads to many autoimmune diseases; the most representative systemic autoimmune disease in humans is systemic lupus erythematosus (SLE or lupus). Therapeutic intervention of SLE and other rheumatic diseases requires a better understanding of the molecular and cellular pathways regulating T cell function. Dr. Hongbo Chi is using a new genetic tool to study this molecular pathway in immune responses and autoimmune diseases with the long-term goal of translating the knowledge gained from these studies into innovative therapeutic strategies. Proteins that may cause RA T cells are the critical components in the initiation and the maintenance
of autoimmune diseases, such as rheumatoid arthritis. Dr. Myung-Shin
Jeon will analyze mice with collagen-induced arthritis to understand
the molecular function of certain proteins in the development of
arthritis. This may help identify novel therapeutic approaches for
the treatment of human autoimmune arthritis and other autoimmune
disorders. The immune system is designed to protect us from infection, but when its regulation is impaired it can give rise to diseases in which normal tissues are damaged. Lupus (SLE) is the prototype of such a disease. The component of the immune system that regulates its activity is a type of white blood cell called a lymphocyte. Like all cells, a complex network of regulatory proteins controls the activation of a lymphocyte. Among the most important of these is one called Ras. Ras functions as a simple molecular switch (“on” versus “off”). Recently, a strain of mice that develop lupus was found to have defective control of Ras. Dr. Adam Mor developed novel tools to study when and where Ras becomes active in living cells. He will apply these tools to lymphocytes from normal and lupus mice to learn what aspects of Ras activation are relevant for the development of the disease. In order to prevent onset of the disease, we must understand the
defects at the molecular level. Learning the basic pathways involved
in the pathology of lupus is a crucial step in the development of
drugs against the disease. In industrialized countries, osteoarthritis affects over one-third
of the adult population. Since cartilage is unable to repair itself,
treatments for osteoarthritis primarily cover up symptoms only.
This had led to efforts to develop alternative means to restore
degenerated cartilage. Over the last few years, research in tissue
regeneration has been bolstered by the discovery that cells in bone
marrow, called mesenchymal stem cells (MSC), are capable of maturing
into several tissues including cartilage. Dr. Anna Spagnoli’s
research is aimed at understanding the mechanisms by which growth
factors regulate MSC cartilage regeneration potential. Among these
growth factors, insulin-like growth factor-I (IFG-I) seems to play
a pivotal role in cartilage regeneration. The primary focus of Dr.
Spagnoli’s study is to define the mechanisms by which IGF-I
determine the cartilage potential of MSC. Identification of such
mechanisms will provide a critical framework to fully implement
and optimize effective MSC gene and cellular therapy in patients
with osteoarthritis. The structural integrity of bone is maintained by the coordinated actions of two cell types, the bone forming osteoblast and the bone resorbing osteoclast. In rheumatoid arthritis (RA), there is an imbalance in the activities of these two cells, with osteoclast resorption predominating. This results in bone loss within the joints leading to joint deformity and pain. The exact mechanisms mediating this imbalance have not been fully elucidated. White blood cells such as T cells not only contribute to inflammation within the RA joint, but have also been implicated in mediating the formation of osteoclasts. There is also evidence to suggest that T cells may modulate osteoblast formation and function. Therefore, T cells represent a potential target for therapeutic intervention to prevent arthritis-induced bone loss. Dr. Nicole Walsh’s study will assess the potential for the
T cells to modulate osteoblast formation and function in arthritis,
using experimental animal models of arthritis. A clearer understanding
of the role of T cells in mediating arthritis-induced bone loss
may lead to the development of novel therapeutic strategies to prevent
bone loss in this disease. The 2005-2006 Sontag Foundation Fellowship award recipient, Xueding
Wang, Ph.D., developed a new technique using laser technology to
provide images of soft tissues such as joints affected by arthritis.
He will test the technique (which has already been demonstrated
successfully in brain images) in animals, comparing the non-invasive
images with physically sectioned tissue to determine the efficacy
of the imaging technique. Alternative to Immunosuppressive Drugs Certain cells that respond to self tissues or organs exist in normal humans; however, their activities are controlled by a cell population called regulatory T cells. The deficit and dysfunction of regulatory T cells cause autoimmune diseases. This novel knowledge provides a possibility that regulatory T cells can replace immunosuppressive drugs to treat autoimmune diseases. Dr. Song Guo Zheng will study the effects of different combinations
of regulatory T cells, generating results that will provide guidance
to choose optimal combination of regulatory T cells in the therapy
for SLE patients. Grant Recipients a Second Year: The Research Continues For the first time this year, the ANRF has awarded a second year
of funding to several scientists. Each submitted a detailed report
outlining the scientific progress made during the first year of
their study and a formal proposal for continuing the work for a
second year. These four researchers were chosen from all grant applicants: Fibrosis is the cycle of damage-healing-scarring-damage, etc. in inflammatory disease. The functions of various proteins and peptides are to direct specific inflammatory cells to the diseased tissue and to regulate formation and breakdown of fibers in scars. Research has shown that fibrosis progresses in some mice, but other affected mice return to normal, suggesting that healing mechanisms exist to end inflammation and clear the scarring, thereby reversing fibrosis. The results of Dr. Kemin Chen’s study will be 1) to determine
if fibrosis derives from dysregulated proteins and peptides in the
study, and 2) to design therapeutic strategies to inhibit development
of fibrosis by blocking the specific proteins and peptides (chemokines
and MMPs). Rheumatoid arthritis is a chronic inflammatory condition affecting almost 1% of the world’s population. The cause of this complex disease is still unknown. However, considerable research interest has focused on the appearance of disease specific autoantibodies that recognize a subset of our own proteins that contain an unusual modification called citrulline. Some of the most specific forms of these autoantibodies recognize citrullinated proteins, appear very early in the disease. One hypothesis is that dysregulation of this citrullination process results in unusually modified proteins that could induce this autoimmune response. In support of this model, a strong association has been discovered between susceptibility to rheumatoid arthritis and mutations in a gene responsible for protein citrullination. Dr. Fast’s lab is studying the mutations in this gene that
may result in changes to the normal activity, regulation, localization,
or specificity of its product, an enzyme that catalyzes protein
citrullination. He is comparing this enzyme and the mutant enzyme
that is associated with rheumatoid arthritis susceptibility to determine
whether these mutations introduce any functional changes into the
activity or regulation of this important enzyme. He is also synthesizing
and studying new small molecules that can inhibit the activity of
the enzyme. In the future, these small molecules could potentially
be used in the design of new drugs to treat rheumatoid arthritis. Systemic lupus erythematosus (SLE) is an autoimmune disease that
is caused by the production of autoantibodies that mediate tissue
damage of target organs, such as the kidney. The autoreactive B
cells that secrete autoantibodies are generated in healthy individuals;
however, they are unable to cause disease because the immune system
is able to effectively regulate these cells. Dr. Christine Grimaldi
will study how the autoreactive B cells of SLE patients bypass the
surveillance mechanisms of the immune system that would normally
silence these cells in healthy individuals. Current treatments for autoimmune diseases such as rheumatoid arthritis
or lupus are based on regulation of an uncontrolled immune system
by immunosuppressive drugs. However, these drugs are often toxic
with undesirable side effects. The development of more advanced
drugs, with strong immunosuppression, low toxicity and few side
effects is necessary. |
