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TARGETING HIF-1α DYSFUNCTION TO TREAT PRESSURE ULCERS IN THE AGED

针对 HIF-1α 功能障碍治疗老年人压疮

基本信息

批准号：
10444745
负责人：
GEOFFREY C GURTNER
金额：
$ 32.57万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444745
关键词：
5 year old Affect Age-Years Aging American Animal Model Animals Back Biopsy Specimen Buttocks Cells Consult Data Defect Deferoxamine Dermis Diabetes Mellitus Drug Delivery Systems Drug usage Elderly FDA approved Family suidae Fibroblasts Functional disorder Gene Targeting Health Care Costs Healthcare Systems Human Hypoxia Impaired wound healing Impairment Incidence Individual Intervention Lead Modeling Molecular Mus Nursing Homes Operative Surgical Procedures Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Prevention Protein Analysis Proteins Research Risk Safety Sampling Signal Transduction Skin Skin Aging Skin Tissue Specialist Stratum corneum System Testing Time Tissues Transdermal substance administration Ulcer United States United States National Institutes of Health Vascular Diseases Work age related aged aging population chronic wound comorbidity decubitus ulcer drug efficacy effectiveness validation efficacy testing healing hydrophilicity hypoxia inducible factor 1 improved neovascularization novel novel strategies novel therapeutic intervention novel therapeutics older patient porcine model preclinical study pressure prevent single cell sequencing skin ulcer skin wound small molecule standard of care transcriptomics wound wound healing

项目摘要

Project Summary Pressure ulcers affect 2.5 million people in the United States and cost the healthcare system an estimated 11.6 billion dollars annually. A major percentage of affected individuals are over sixty-five years of age and this number is growing rapidly in the United States. A greater incidence of immobility, vascular disease and diabetes is commonly seen in aged populations and places them at an increased risk for developing pressure ulcers. Thus, there is a pressing need to develop new therapies that will effectively treat pressure ulcers in the aged. With prior NIA support, we have found that aging is characterized by the progressive loss of critical molecular and cellular pathways responsible for normal wound healing, specifically hypoxia-inducible factor 1-alpha (HIF- 1α). We have also identified that these changes can be reversed using an FDA-approved small molecule drug, deferoxamine (DFO). Building on our preliminary data, we will first define the aberrations of HIF-1α in healthy, unwounded skin from young and aged patients (Specific Aim 1). We will then confirm the HIF-1α signaling dysfunction in pressure ulcers using biopsy specimens from both young and aged patients. (Specific Aim 2). To define the alterations in hypoxia signaling within the skin cells of young versus aged patients, we will subject the collected tissue for protein analysis and single cell sequencing. We will then determine the optimal delivery system for DFO through both intact stratum corneum as required for treating pressure ulcers in a porcine model (Specific Aim 3). This large animal model is selected since porcine skin has significant similarities to the human skin. Our results will validate the effectiveness of our drug delivery system and provide a novel strategy to deliver other hydrophilic small molecule drugs across intact human skin. Taken together, this pre-clinical study will lay the groundwork for a pilot human trial targeted at treating pressure ulcers with the transdermal DFO delivery system, which will for the first time provide a pharmacologic therapy to treat pressure ulcers in aged patients.

项目概要美国有 250 万人受压疮影响，医疗保健系统损失估计为 11.6 每年十亿美元。大部分受影响的人年龄超过 65 岁，这在美国，这一数字正在迅速增长。不动、血管疾病和糖尿病的发生率更高常见于老年人群，使他们患压疮的风险增加。因此，迫切需要开发有效治疗老年人压疮的新疗法。在 NIA 之前的支持下，我们发现衰老的特点是关键分子的逐渐丧失以及负责正常伤口愈合的细胞途径，特别是缺氧诱导因子 1-α（HIF- 1α）。我们还发现，使用 FDA 批准的小分子药物可以逆转这些变化，去铁胺（DFO）。基于我们的初步数据，我们将首先定义 HIF-1α 在健康、年轻和老年患者未受伤的皮肤（具体目标 1）。然后我们将确认 HIF-1α 信号传导使用来自年轻和老年患者的活检标本来研究压疮的功能障碍。（具体目标 2）。到为了定义年轻患者与老年患者皮肤细胞内缺氧信号的变化，我们将研究收集组织用于蛋白质分析和单细胞测序。然后我们将确定最佳交付根据治疗猪模型压疮所需的 DFO 系统穿过完整的角质层（具体目标 3）。选择这种大型动物模型是因为猪皮肤与人类皮肤具有显着相似性皮肤。我们的结果将验证我们的药物输送系统的有效性，并提供一种新的策略来输送其他亲水性小分子药物穿过完整的人体皮肤。总而言之，这项临床前研究将奠定为通过透皮 DFO 给药治疗压疮的试点人体试验奠定基础该系统将首次提供治疗老年患者压疮的药物疗法。