Project Description Narrative:
The immune system diseases, including leukemia/lymphoma, immunodeficiency, and autoimmune diseases, are a serious health threat in Wisconsin and worldwide. It is estimated that about 20% of the population, or one million people in Wisconsin, suffer from primary immune deficiency or autoimmune diseases. In addition, about 1,000 people in Wisconsin are expected to develop leukemia/lymphoma per year. B cells are an essential component of the adaptive immune system. B cell development and function are tightly controlled by multiple signals, including those emanating from the pre-B cell receptor (BCR) or BCR. Moreover, signals orchestrated by the pre-BCR/BCR serve as guardians against B-cell transformation and abnormal function. Impairment of pre-BCR/BCR signaling components leads to B cell leukemia/lymphomas, immune deficiency, or autoimmune diseases.
Despite tremendous advances in the understanding of the signal transduction of pre-BCR/BCR, signaling components of pre-BCR/BCR are far from completely identified. Rap1b is a ubiquitously expressed member of the Ras superfamily of small GTP binding proteins. Rap1b is an active signaling molecule and has been implicated in a variety of cellular processes. Preliminary studies have demonstrated that Rap1b is expressed in B cells throughout development and becomes the active GTP-bound form upon engagement of the BCR. The researchers’ preliminary analysis of Rap1b-deficient mice has revealed developmental defects in B cells. Although substantial evidence points to a potential role for Rap1b in B cell biology, its exact role in the development and function of B cells is unknown.
The goal of this project is to use Rap1b-deficient mice to determine the roles of Rap1b in B cell development and function, and to study the mechanism by which Rap1b regulates B cell biology. Understanding the roles for Rap1b in B cell biology may provide new clues to the molecular pathogenesis of leukemia/lymphoma, immunodeficiency, and autoimmune diseases, and help identify new targets for specific therapies.