The Role of mDia1 in the Aberrant Innate Immune Signaling in del(5q) Myelodysplastic Syndromes
Abstract
Scientific Objective and Rationale: Myelodysplastic syndromes (MDS) are a group of diseases affecting bone marrow and blood with an increased risk of developing acute leukemia. MDS is one of the significant health-related challenges with the rapidly aging population worldwide. Many genomic abnormalities are associated with MDS with deletion of chromosome 5 being the most common. Our recently published work demonstrated that loss of mDia1, a protein with its encoding genes located at chromosome 5, led to the activation of the innate immune response through an aberrant overexpression of CD14 on granulocytes (one of blood cell types), which accelerate the development of MDS in mDia1 deficient mice. CD14 granulocytic overexpression is also observed in MDS patients with decreased mDia1 expression. Based on this study, we hypothesize that CD14-induced abnormal immune response is critical in the pathogenesis of MDS. Our proposed studies aim to discover the pathogenesis of MDS related to the deregulated innate immune system, which could provide important clues for the development of novel therapeutic strategies for the clinical care of MDS. Principal Investigator s Career Goals: I have a long interest in the basic biology of hematopoiesis and how deregulation of genes involved in normal hematopoiesis contributes to the pathogenesis of blood cancers. The Peer Reviewed Cancer Research Program Career Development Award is going to prepare me for the next phase in my career as an independent investigator. It is going to give me critical bridge time in an environment where I can rapidly become acquainted with scientific and intellectual skills that are critical in my future career in blood cancer research. During the stage of the Career Development Award, I will continue to develop current knowledge and skills in the field of blood cancers through a variety of structured and self-motivated activities. My career goal is to obtain the scientific and intellectual skills necessary to become a successful, independent physician scientist and investigator at the forefront of blood cancer research. Ultimate Applicability of the Research: Successful accomplishment of this project will be helpful to patients with MDS. Supported by our study and many others, the abnormal immune signaling is increasingly being recognized as important factors in the development of MDS. In this project, we propose to target many abnormal immune signaling pathways in MDS using knowledge obtained from mDia1 knockout mouse model, which could provide important clues for the development of novel immunotherapeutic strategies for the clinical care of MDS patients. We expect that the novel inhibitors tested in the proposal will be quickly translated to clinical trials. Furthermore, our study also helps to understand the mechanism of action for these immune modulators in MDS by repressing the abnormal immune response. Military Beneficiaries: Active duty military personnel have a significantly increased chance of being infected, which provides sources of so-called "pathogen associated molecular patterns" (PAMPs). They also have increased risk of irradiation exposure, which provides sources of "damage associated molecular patterns" (DAMPs). Both PAMPs and DAMPs are critical to trigger the abnormal immune responses that lead to the development of MDS. Therefore, our proposed research is particularly important and disproportionately represented in the military setting.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510335
Entities
People
- Peng Ji
Organizations
- Northwestern University
- United States Army