Targeting neutrophils to harness myeloid responses for wound healing Chronic wounds represent a significant health problem in the United States. Delayed or non-resolving inflammation is a hallmark of the chronic wound and is sustained by myeloid cell accumulation and upregulated myelopoiesis. Metabolic conditions such as obesity contribute to this growing problem and influence myeloid response to wounds. The central hypothesis of this proposal is that obesity and diabetes dysregulate myeloid responses and thereby impairs wound healing. Our preliminary study using mouse models suggests a mechanistic link of neutrophil clearance in the bone marrow with myelopoiesis. We propose a translational study involving both mouse models and human specimens with three Specific Aims: In Aim 1, we will determine the mechanism by which neutrophil clearance in the bone marrow regulates myelopoiesis, with the hypothesis that neutrophils release extracellular vesicles that regulate myelopoiesis during their clearance. In Aim 2, we will determine the mechanism of inhibited neutrophil clearance in the bone marrow in chronic wounds and obesity, with the hypothesis that chronic wounds and obesity increase glutamine utilization in neutrophils and inhibit their clearance in the bone marrow. In Aim 3, we will bioengineer a nano-drug that target neutrophils and modify myeloid response. To achieve this, we will utilize a well-defined versatile telodendrimer to selectively deliver glutaminase inhibitor to neutrophils and will test the nano-drug in the preclinical mouse model of impaired wound healing in obesity. The proposed experiments will improve knowledge of myeloid responses during wound healing. The impact of these studies lies in the potential for translation to therapies that stimulate healing responses in hard-to-heal wounds. Also, the studies could lead to the development of assays that involve monitoring blood neutrophil survival as cellular biomarkers to aid in the selection of treatment options for patients with chronic wounds and/or obesity. Project Summary/Abstract