Ribosome Biogenesis Defects as an Underlying Mechanism and a Therapeutic Target of Fanconi Anemia
Abstract
Bone marrow failure (BMF) typically results from a defect in hematopoietic stem cells (HSCs), which are the cells that give rise to the various lineages of blood cells. BMF can either be inherited or acquired, and can necessitate HSC transplantations for treatment, and increase the risk of death. The most frequently observed inherited bone marrow disease is Fanconi anemia (FA). Therefore, elucidation of the mechanism underling BMF in FA is highly important for understanding what causes it, and for possible development of improved diagnostic, preventative, and/or treatment strategies for bone marrow failure that may be extensible to other BMF syndromes. At present, it is widely held that Fanconi anemia is caused by a defect in the cell’s ability to repair damage to its genetic material. It is unclear, however, how this defect causes bone marrow failure. Here, we instead propose the paradigm-shifting concept that BMF in FA is caused by defective formation of ribosomes, which is the cellular machinery that produces proteins encoded by the genetic material (DNA), to mediate various cellular functions. Defective formation of ribosomes is termed a “ribosomopathy.” Our objective in this proposal is to understand how inactivation of FA proteins, due to mutations in FA genes, leads to a defect in the formation of ribosomes and to test a possible future treatment for BMF in FA. This will be accomplished in two parts. In the first part, we will determine whether defective formation of ribosomes in FA is due to a loss of suppression of potentially disruptive structures in the DNA that produces ribosomal RNA (rRNA), which is a key component of ribosomes. This includes determining whether this process is defective in HSCs with deficiencies for FA genes/proteins, as a basis for understanding the potential causes of BMF in FA. In the second part of the proposal, we will introduce genes for ribonucleases, which can possibly remove the disruptive structures in genes that encode ribosomal RNA, including in HSCs. In this way, we will explore a novel preventative and/or treatment strategy for bone marrow failure in Fanconi anemia. It is important to point out that other BMF diseases, including Diamond-Blackfan anemia, Swachman-Diamond syndrome and dyskeratosis congenita are also ribosomopathies. The proposed research project is highly innovative because it seeks to establish a new mechanism, defective formation of ribosomes, as the actual basis for BMF in FA. Doing so would also be innovative because it would establish commonalities with the other major inherited bone marrow failure (IBMF) diseases. Another particularly innovative aspect of this proposal is that not only do we identify a new cause for BMF in FA, but this is the basis for initial work to establish new strategies to prevent and/or treat BMF in this disease. Innovation is also strengthened by utilization of cutting-edge molecular techniques/approaches and mouse models. The research project proposed here is expected to have a major impact on the care and quality of life of patients with bone marrow failure. In the short term, this should lead to an improved understanding of what causes the most common inherited BMF disease, and should also unify it with several other inherited BMF diseases and demonstrate their commonalities. The work proposed here should also identify a possible new treatment for BMF in FA. In the long term, the identification of a new cause for BMF in FA, based upon defective formation of ribosomes, may provide a basis for more sensitive and/or effective diagnostic tests for FA and possibly for related diseases. Early detection, as well as having a means to determine which patients have a greater propensity for bone marrow failure, should decrease deaths and improve quality of life for patients. In particular, development of a way to improve HSC function may be the basis for a means to prevent bone marrow failure in FA. This should be of great benefit to pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110148
Entities
People
- Gang Huang
Organizations
- United States Army