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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.

靶向中性粒细胞利用髓细胞反应促进伤口愈合