Targeting neutrophil clearance to harness myeloid responses for wound healing.

以中性粒细胞清除为目标，利用骨髓反应促进伤口愈合。

基本信息

批准号：
10585425
负责人：
Norifumi Urao
金额：
$ 32.6万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585425
关键词：
Biological Markers Biomedical Engineering Bone Marrow Cell Death Cessation of life Chronic Data Diabetes Mellitus Drug Targeting Economic Burden Genetic Models Glutaminase Glutamine Goals Health Hematopoietic stem cells Homing Human Impaired healing Impaired wound healing Inflammation Inflammatory Knowledge Leukocytes Link Macrophage Metabolic Metabolism Monitor Mus Myelogenous Myeloid Cells Myelopoiesis Obese Mice Obesity Organ Patients Pre-Clinical Model Process Quality of life Research Risk Selection for Treatments Skin wound healing Specimen Testing Tissues Translations Treatment Cost United States Up-Regulation Wound models aged assay development chronic wound comparative experimental study extracellular vesicles genetic manipulation healing improved in vivo inhibitor insight loss of function mouse model nanocarrier nanodrug neutrophil novel novel drug class novel marker pre-clinical progenitor regenerative response skin wound socioeconomics translational potential translational study vesicular release wound wound healing wound response

项目摘要

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.

靶向中性粒细胞以利用骨髓反应促进伤口愈合慢性伤口是美国的一个重大健康问题。延迟或未解决炎症是慢性伤口的标志，由骨髓细胞积累和上调维持骨髓生成。肥胖等代谢状况导致了这一日益严重的问题并影响骨髓对伤口的反应。该提案的中心假设是肥胖和糖尿病导致骨髓细胞失调反应，从而损害伤口愈合。我们使用小鼠模型进行的初步研究表明骨髓中中性粒细胞清除与骨髓生成的机制联系。我们提出一项转化研究涉及小鼠模型和人类标本，具有三个具体目标：在目标 1 中，我们将确定骨髓中的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细胞生成的细胞外囊泡。在目标 2 中，我们将确定慢性伤口和肥胖症中骨髓中中性粒细胞清除受到抑制的机制，假设慢性伤口和肥胖会增加中性粒细胞中谷氨酰胺的利用并抑制其骨髓中的清除。在目标 3 中，我们将通过生物工程设计一种纳米药物，以中性粒细胞为目标并修饰骨髓反应。为了实现这一目标，我们将利用明确的多功能末端树枝状聚合物来选择性地提供中性粒细胞谷氨酰胺酶抑制剂，并将在伤口受损的临床前小鼠模型中测试纳米药物治愈肥胖。拟议的实验将提高对伤口期间骨髓反应的了解康复。这些研究的影响在于转化为刺激愈合疗法的潜力难以愈合的伤口的反应。此外，这些研究可能会导致涉及的检测方法的开发监测血液中性粒细胞存活率作为细胞生物标志物，以帮助选择患者的治疗方案患有慢性伤口和/或肥胖。