Lab Interests
Our laboratory investigates the molecular mechanisms of and develops specific therapies to treat autoimmune disease, with a focus on rheumatoid arthritis (RA) and multiple sclerosis (MS).
Our major objectives include:
3. To develop methods to induce antigen-specific tolerance.
4. To investigate the role of tyrosine kinases in the pathogenesis of autoimmune disease.
Overview
Autoimmune diseases affect 3% of the world population, yet the autoantigens involved in and mechanisms underlying the initiation, natural remission, and perpetuation of most autoimmune diseases remain poorly understood. The major objectives of our research are to understand the pathogenic mechanisms underlying and to develop fundamental treatments to treat autoimmune diseases.
Current therapies for autoimmune diseases utilize agents that globally suppress or alter immune function. Such therapeutics are not curative and result in only mild slowing of disease progression. Great clinical needs exist for fundamental therapies that do not cause global immune suppression. We are applying proteomic, lipidomic and genomic technologies to study the pathogenesis of and to develop specific therapies for RA and MS.
Figure. Proteomic, lipidomic and genomic analyses to investigate the mechanisms underlying autoimmune disease, and to develop specific therapies.
(1) To develop and apply proteomic and lipidomic technologies to define the targets of the autoimmune responses in RA and MS.
The autoimmune targets in RA and MS remain poorly understood.
Recent data suggest that autoimmunity in RA may be directed against citrullinated synovial joint proteins, although specific targets have not been fully elucidated. Citrullination (deimination) of synovial proteins results from post-translational conversion of arginine residues to citrulline by peptidyl-arginine deiminases.
Data suggest that MOG and MBP may represent important autoimmune targets in MS, and we have recently demonstrated that myelin lipids are prominent targets of the autoimmune response in MS.
We are developing and applying proteomics and lipidomics technologies to further define the autoantigens in RA and MS.
(2) To study the molecular mechanisms of immune tolerance, including the mechanisms regulating the initiation, natural remission and progression of autoimmunity.
Questions in autoimmunity that are being studied include:
Why is there discordance in the development of autoimmunity between genetically identical humans and mice?
What mechanisms underlie natural remission?
What molecular events lead to progressive disease?
How do innate immune stimuli influence the development and progression of adaptive autoimmune responses?
(3) To develop specific therapies to treat autoimmune disease.
Antigen-specific tolerizing therapies attenuate autoreactive lymphocytes targeting autoantigens.
We are developing next generation tolerizing vaccines and studying their mechanisms of action.
(4) To investigate the role of tyrosine kinases in the pathogenesis of autoimmune disease.
We demonstrated that the tyrosine kinase inhibitor imatinib powerfully treats rodent models of RA. Imatinib inhibits multiple tyrosine kinases and cellular responses, and we are investigating the role of specific tyrosine kinases and cellular responses in the pathogenesis of RA and other autoimmune diseases.
We are studying use of tyrosine kinase inhibitors as an approach to treat autoimmune disease.
(5) To study the biology of and to develop strategies to promote cartilage regeneration for the treatment of RA and osteoarthritis.
We are characterizing the mechanisms of cartilage degeneration in RA and OA.
We are developing cartilage protective and regenerative strategies for the treatment of RA and OA.
