How Does a DNA Helicase Regulate Blood Cell Development and Disease?
Abstract
The scientific objective and rationale for the proposed project: This project seeks to understand how a protein called RECQL4 works in blood cells. Mutations in the DNA of the gene of RECQL4 cause a disease in humans called Rothmund-Thomson Syndrome. The patients get cancer (bone cancer, blood cancer, skin cancer) at a much higher rate than people without mutations in RECQL4. While this is a very rare disease, it demonstrates that RECQL4 is very important in human cancers and that mutations in RECQL4 can lead to the development of cancer. We now know that rare human cancer syndromes have identified important information relevant to all types of cancer. I am interested in how RECQL4 affects blood cells. As Rothmund-Thomson syndrome is rare in humans, I have used a genetically modified mouse to understand the role of the RECQL4. When the RECQL4 protein was removed, the mice rapidly developed bone marrow failure, demonstrating that RECQL4 was essential to keep our blood system functioning normally. The scientific objective is to understand how mutations in RECQL4 can lead to the development of cancer, and I will focus on blood cancers for this work. Describe the Principal Investigator s (PI s) career goals in cancer research: My career goal is to improve the treatment and outcomes for patients with myeloproliferative disease and bone cancer (osteosarcoma) through the application of innovative models to identify and test new treatment approaches. I make mouse models of human cancer to identify new therapies and test them so that we can accelerate the transition of research to patient benefit. How will the award advance the PI s career in at least one of the Fiscal Year 2014 (FY14) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas? I actively research the FY14 PRCRP areas of blood cancers, genetic cancer research, and myeloproliferative diseases. This award will allow me to extend my recent studies to develop a better understanding of the role of RECQL4 in blood system function and how RECQL4 mutations affect response to chemotherapy and radiation. How does the research and career development plan support the PI in attaining these goals? The research will allow me to extend our understanding of RECQL4 in blood system function and treatment response. My career development plans emphasize a focus on asking human patient relevant questions. The designated mentor for this application is a leading clinician-researcher in Australia and has a proven record in clinical translation of research. Describe the ultimate applicability of the research: This research will be applicable to patients with Rothmund-Thomson Syndrome directly, and more broadly applicable to patients with blood cancers. More generally, it will provide fundamental insights into the maintenance of chromosome stability relevant to a wider range of cancers and myeloproliferative disorders. What types of patients will it help, and how will it help them? Patients with blood cell cancers (leukemia, myeloproliferative diseases) are the most likely to benefit. Additionally, those with tumors where genome stability is a feature of the tumor (chromosomal instability, aneuploidy) will also benefit. What are the potential clinical applications, benefits, and risks? If the research is too basic for clinical applicability, describe the interim outcomes expected and their applicability to the field: Clinical applications are a better understanding of Rothmund-Thomson syndrome and new models of this disease for preclinical testing. The proposal will let us understand how mutations in RECQL4 affect response to chemotherapy and radiation, which may lead to ways to either increase the effects of these treatments or protect cells that would otherwise be impacted during therapy. What is the projected time it may take to achieve a clinically relevant outcome? The information will be directly relevant to Rothmund-Thomson syndrome patients cur
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510315
Entities
People
- Carl R Walkley
Organizations
- United States Army