Project 467089

Haematopoetic stem cells (HSCs) which reside in the bone marrow differentiate into various blood cell types including neutrophils and macrophages that are important for first line of defence against infections. HSCs can accumulate mutations, particularly with aging termed Clonal Haematopoeisis of Indeterminate Potential (CHIP). Accumulation of such mutations within blood cells can promote their increased proliferation which could lead to cancer. Additionally mutations can alter various other functions of blood cells leading to inflammation and increased risk of cardiovascular diseases. When CHIP mutations occur within macrophages and neutrophils the ability of our immune system to combat infections can be compromised. While the detrimental effect of CHIP mutations on macrophages has been studied, the consequence of CHIP mutations in neutrophils which are the most abundant cell type in the blood is not well understood. Therefore, the specific objective of our study is to examine the role of CHIP mutations on neutrophil function and understand how this correlates to our ability to combat infections. We have engineered neutrophil cell lines that express or lack some of the common CHIP mutations such as TET2. We will evaluate neutrophil fucntion in these two cell types such as their ability to engulf bacteria (phagocytosis), produce various molecules such as reactive oxygen species and look at the differential expression of other genes and proteins. The long-term aim of this study is to indentify therapeutic targets that can be used to rescue neutrophil function, particularly in older adutls that harbor CHIP mutations, and thereby reduce their risk of infection.