Objective
The objective of this research is to test if DOCK2 is a suitable therapeutic target for T1D, SLE, and MS. We will test it using three sub-aims: 1) Using animal models, we will test if small molecule inhibitors of DOCK2 delay/prevent autoimmunity; 2) In DOCK2-inhibitor treated animals, we will assess if the immune cell infiltration in tissues is affected qualitatively and quantitatively; and 3) using publicly available datasets, we will evaluate if DOCK2 is active and associated with disease-affected tissues. Together, our objective is to translate DOCK2 inhibition as a disease modifying therapy.
Background Rationale
Autoimmune diseases such as Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Multiple Sclerosis (MS), are caused by immune system attacking the patient’s own organs. In patients with these diseases, immune cells including killer T cells, helper T cells, and antibody producing B cells enter the organs and cause their destruction. Immune cells sense cues from tissues that serve as beacons for them to follow and enter tissues prior to destruction. These beacons are called chemokines, and the movement mediated by them is called chemotaxis. Immune cells use several key molecules to mediate chemotaxis and therefore infiltration into tissues. A protein called DOCK2 mediates this movement in immune cells. In our preliminary studies, elevated levels of DOCK2 were found to be associated with increased tissue infiltration by immune cells. We also showed that two small molecules that inhibit DOCK2 were able to block immune cell movement. Therefore, in this project, we will test whether DOCK2 inhibition is a suitable therapeutic strategy for treating autoimmune diseases.
Description of Project
Autoimmune diseases such as Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Multiple Sclerosis (MS), are caused by immune system attacking the patient’s own organs. In patients with these diseases, immune cells including killer T cells, helper T cells, and antibody producing B cells enter the organs and cause their destruction. A promising strategy to treat autoimmune diseases is to block the movement of immune cells that is required to enter normal tissue prior to destruction. Our preliminary studies have suggested that a key molecule called DOCK2 is responsible for mediating immune cell infiltration into tissues. In this proposal, we will test whether DOCK2 is a suitable therapeutic target to treat autoimmune diseases, including T1D, SLE, and MS. We will use mouse models of these diseases to test if small molecule inhibitors of DOCK2 can block infiltration of immune cells into tissues, thereby preventing and/or delaying autoimmunity. We will also analyze publicly available patient datasets to evaluate if this pathway is active in tissues affected by the autoimmune diseases. If successful, our research will establish DOCK2 as a target for developing novel therapies to treat multiple autoimmune diseases.
Anticipated Outcome
We anticipate that in animal models, treatment with DOCK2 inhibitors will delay and/or prevent autoimmunity significantly. Moreover, we anticipate that DOCK2 inhibitors will be efficacious against T1D, SLE, and MS, indicating that it is a common mechanism behind autoimmunity. We expect that our research will develop DOCK2 inhibition as a novel therapeutic strategy for multiple autoimmune diseases.
Relevance to T1D
In this project, we will test whether the DOCK2 pathway is active in Type 1 Diabetes, and whether it is shared between T1D, SLE, and MS. The success of our research will develop a novel therapeutic strategy for T1D.