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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.

项目总结