2025 Recipients of the Gary S. Gilkeson Career Development Award
Jared Graham, PhD
Mentor(s): Karen Gould, Ph.D., MEd
Institution: University of Nebraska Medical Center
Project Title: Assessing the Role of SHP2 on B Cell Proliferation in a Lupus Mouse Model
Project Summary: Lupus is a disease affecting 1.5 million Americans. While the exact causes of lupus are unclear, lupus is characterized by the production of autoantibodies that target the patient’s proteins and DNA. These autoantibodies are produced by autoreactive B cells that are deleted in healthy individuals and are deposited in organs and tissue leading to inflammation and damage. The mechanisms through which these autoreactive B cells survive in lupus patients are unknown. Using a mouse model of lupus that develops increased levels of hyperactivated B cells and autoantibodies, our lab observed that the Src homology region 2 domain-containing phosphatase-2 (SHP2), a protein that was thought to restrict B cell development, is required for B cell proliferation. SHP2 is a negative regulator of T cell proliferation, but its role in B cell development and autoimmunity is less clear. We treated B cells from our lupus mouse model with a chemical inhibitor of SHP2 and observed decreased B cell proliferation as well as decreased activity of proliferative proteins in B cells. These findings led us to our central hypothesis that SHP2 enhances the activity of proteins associated with proliferation in B cells. As our previous findings were determined in B cells that were removed from the mouse prior to the addition of the inhibitor, we will seek to identify the impact of SHP2 on B cell proliferation and autoantibody production inside the mouse. To do this, we will inject our mice with a SHP2 inhibitor and monitor total numbers of immune cells, B cell proliferation in the spleen, and autoantibody production. Our second aim will identify SHP2 interacting proteins in B cells as well as protein activity modified by SHP2. For this, we will use mass spectrometry to identify SHP2 protein-protein interactions. Completion of this project will clarify the mechanisms through which autoreactive B cells survive and proliferate in lupus patients as well as identify new human therapeutic targets.
Jacquelyn Nestor, M.D., Ph.D
Mentor(s): Andrew Luster, M.D., Ph.D.; Alexandra-Chloé Villani, Ph.D.; April Jorge, MD
Institution: Massachusetts General Hospital
Project Title: Unraveling CD4+ T cell imbalance in SLE
Project Summary: There are many types of immune cells that travel throughout the human body to protect us from damage and infections. Each immune cell has its own job and role in responding to attacks on the body. Sometimes immune cells get confused and attack our bodies by mistake, causing autoimmune diseases like lupus. To understand why these immune cells misbehave we will study individual immune cells from the blood of healthy patients and those with lupus and other autoimmune diseases. By comparing these cells across diseases, we can reveal abnormalities that are shared across autoimmunity and highlight those that are unique to lupus. These irregularities can potentially serve as targets for new medications to help treat lupus and other autoimmune conditions. One of the cell types we are interested in are regulatory T cells (Tregs), whose job is to control other immune cells such as T effector cells (Teffs) that cause inflammation and damage throughout the body. We have already found two unique types of Tregs increased in patients with lupus, which we will investigate further, including studying their effect on the other types of immune cells, such as Teffs. We will also test a new treatment in a mouse model of lupus, which we hypothesize works by increasing the number of protective Tregs and decreasing inflammation. By better understanding how immune cells like Tregs and Teffs work in healthy patients and how they stop working in autoimmune diseases, we can design new treatments specifically targeted to fix these immune cells and help improve the lives of patients with autoimmune diseases and more specifically patients with lupus.