Regulation of Programmed Necrosis and Bone Marrow Failure
[Technical Report, Final Report]
Vanderbilt University Medical Center
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Blood cell production is a highly dynamic process, designed to respond to stresses such as infection or bleeding over the entire lifespan of a person or animal. During normal conditions, there is a careful balance between blood cells made and blood cells removed due to aging or damage. A highly regulated process called programmed cell death removes cells, and bone marrow failure occurs when more cells are removed than can be replaced. There are two major pathways of programmed cell death apoptosis and necrosis. Simply described, apoptotic cells implode in an immune silent process, and necrotic cells explode, activating an inflammatory response. In bone marrow failure disorders, necrotic death of bone marrow cells increases normal bone marrow damage by amplifying the pathological inflammatory response. We hypothesize that increased necrotic cell death initiates a feed forward inflammatory process that kills normal bone marrow, and that targeting this programmed necrotic cell death could be used for therapeutic benefit. This proposal is focused on 1 determining how necrotic cell death impacts the surrounding normal bone marrow, and 2 determining whether inhibiting necrosis can rescue bone marrow failure in mouse models of MDS.
- Medicine and Medical Research