Chemo- and radiotherapy are extensively used to treat various hematological malignancies and solid tumors. Neutropenia and related infection are the most important dose limiting toxicities of these anti-cancer treatments, impacting on quality of life and clinical outcomes, with the potential to cause death. Neutropenia- related pneumonias are involved in 40% infection at a site other than blood alone, and are directly caused by the lack of neutrophils in infected lungs to clear the invading pathogens. They are usually treated with broad- spectrum antibiotic therapy and granulocyte colony-stimulating factor (G-CSF) therapy. However, not all patients respond to these treatments and G-CSF therapy is often associated with side-effects such as bone pain, headache, fatigue, nausea, and higher risk of getting leukemia. In addition, G-CSF therapy doesn't work before the bone marrow is recovered. The long-term goal of this project is to explore another strategy for treating/preventing neutropenia-related pneumonia - via enhancing neutrophil functions (e.g. recruitment, survival, and bacteria killing) in neutropenic patients. We tried to achieve this by elevating intracellular PtdIns(3,4,5)P3 signaling pathway which has been implicated in a variety of neutrophil functions. In the last funding period, we successfully established that augmenting PtdIns(3,4,5)P3 signaling via PTEN disruption enhances neutrophil function and host defense in neutropenia-associated pneumonia. This finding confirms the validity of the PtdIns(3,4,5)P3 pathway as a therapeutic target. Nevertheless, PTEN disruption has been implicated in tumorigenesis of numerous solid and hematologic cancers, thus PTEN is not considered an ideal therapeutic target. Recently, we reported that PtdIns(3,4,5)P3 signal in neutrophils can also be elevated by disrupting InsP6K1, an enzyme responsible for the synthesis of InsP7, a cytosolic molecule that negatively regulates PtdIns(3,4,5)P3 signaling. Our preliminary data demonstrated that InsP6K1 deficient neutrophils possessed an enhanced bacteria killing capability and their recruitment to the inflamed lungs was augmented (in non-neutropenic mice). Importantly, homozygous InsP6K1 KO mice were viable and did not display any gross physical or behavioral abnormalities. No tumors of any kind was discovered in these mice. Based on these intriguing results, we hypothesize that disruption of InsP6K1 should be a legitimate therapeutic strategy for the treatment of neutropenia-related pneumonia. In this proposed research, we will directly examine whether InsP6K1 disruption can augment neutrophil recruitment and survival in neutropenia-related pneumonia (Aim I), enhance neutrophil bacterial killing capability in neutropenia-related pneumonia (Aim II), and alleviate the severity of neutropenia-related pneumonia (Aim III). In addition, since alveolar macrophages also play a critical role in host defense against respiratory tract infections, whether disruption of InsP6K1 can enhance the function of alveolar macrophages will be investigated (Aim IV).
Experiments proposed in this study will provide insight into the mechanism of action of InsP7 and InsP6K1 in modulating neutrophil and macrophage function in lung infection and inflammation, with the ultimate goal of solidifying InsP6K1 and related pathways as novel therapeutic targets for treatment of neutropenia-related pneumonia. This will be an important and necessary complementation to the current antibiotic and G-CSF therapies. In addition, although we focus on neutropenia-related pneumonia in this application, the same strategy can be readily applied to other neutropenia-related infectious diseases.
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