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

项目摘要 压力性溃疡影响美国250万人，估计医疗保健系统花费11.6 每年10亿美元。大部分受影响的人年龄在65岁以上， 这个数字在美国迅速增长。行动不便、血管疾病和糖尿病的发病率更高 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。 在先前的NIA支持下，我们发现衰老的特征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-1 α）。 1α）。我们还发现，这些变化可以使用FDA批准的小分子药物逆转， 去铁胺（DFO）。基于我们的初步数据，我们将首先定义健康人， 年轻和老年患者的未受伤皮肤（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研究压疮功能障碍。（具体目标2）。到 为了确定年轻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 根据治疗猪模型中压力性溃疡的需要，用于DFO通过两个完整角质层的系统 （具体目标3）。选择这种大型动物模型是因为猪皮肤与人皮肤具有显著的相似性。 皮肤我们的研究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， 其他亲水性小分子药物穿过完整的人体皮肤。总之，这项临床前研究将奠定 DFO透皮给药治疗压疮的人体试验的基础 系统，这将首次提供药物治疗，以治疗老年患者的压力性溃疡。

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.