Targeting neutrophil clearance to harness myeloid responses for wound healing.

以中性粒细胞为靶点利用髓系反应促进伤口愈合 在美国，慢性伤口是一个严重的健康问题。延迟或未解决 炎症是慢性创面的标志，由髓系细胞积聚和上调持续。 骨髓再生。代谢疾病，如肥胖，导致这种日益严重的问题，并影响髓系 对伤口的反应。这一提议的中心假设是肥胖和糖尿病导致髓系失调。 反应，从而损害伤口愈合。我们用小鼠模型进行的初步研究表明 骨髓中性粒细胞清除与骨髓生成的机制联系。我们建议进行一项翻译研究 涉及小鼠模型和人类标本，具有三个特定目标：在目标1中，我们将确定 骨髓中性粒细胞清除调节骨髓生成的机制，假设 中性粒细胞在清除过程中释放调节骨髓生成的细胞外小泡。在目标2中，我们将 确定慢性创伤和肥胖患者骨髓中性粒细胞清除受抑的机制， 假设慢性创伤和肥胖增加了中性粒细胞对谷氨酰胺的利用，并抑制了他们的 在骨髓中清除。在目标3中，我们将生物工程一种以中性粒细胞为靶点的纳米药物并将其 髓系反应。为了实现这一点，我们将利用定义良好的多功能端粒来选择性地提供 谷氨酰胺酶抑制剂对中性粒细胞的影响，并将在临床前创伤小鼠模型中测试纳米药物 治疗肥胖症。拟议中的实验将提高对创伤过程中髓系反应的了解。 治愈。这些研究的影响在于转化为刺激治愈的疗法的可能性。 对难以愈合的伤口的反应。此外，这些研究还可能导致开发涉及以下内容的分析方法 监测血液中性粒细胞存活率作为细胞生物标记物帮助患者选择治疗方案 有慢性伤口和/或肥胖。

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.