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Targeting Senescence to Improve Wound Healing in Aging

靶向衰老以改善衰老过程中的伤口愈合

基本信息

批准号：
10729963
负责人：
Daniel Sam Roh
金额：
$ 24.3万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729963
关键词：
Acute Affect Aging Anti-Inflammatory Agents Apoptosis Attenuated Award CDKN2A gene Caring Cell Aging Cell Communication Cell Proliferation Cells Clinical Trials Coculture Techniques Collagen Data Data Analyses Deposition Dermal Dichloromethylene Diphosphonate Economics Elderly Excision Extracellular Matrix Fibroblasts Gene Proteins Genetic Goals Growth Heterogeneity Human Imaging Techniques Impaired healing Impaired wound healing Impairment Longevity Macrophage Mammals Mentorship Modification Morbidity - disease rate Multiple Wounds Mus Operative Surgical Procedures Organism Patient risk Patients Phenotype Physicians Plastic Surgeon Predisposition Process Production Protein Biosynthesis Regulation Resistance Role Scientist Signal Transduction Skin wound healing Sorting Spatial Distribution Testing Therapeutic Time Tissues Training Translational Research United States Wound Infection acute wound age group age related aged angiogenesis attenuation cell type chronic wound data visualization design improved middle age mortality necrotic tissue novel older patient reconstitution response restoration senescence single-cell RNA sequencing skin wound stressor subcutaneous targeted treatment tissue injury transcriptomics wound wound care wound closure wound healing wound response

项目摘要

Impaired or delayed wound healing is a major problem affecting primarily older adults, millions of older adults in the United States are affected per year. Delayed wound healing increases aged patients’ risk of chronic wounds, wound infections, and tissue necrosis, resulting in significant morbidity and mortality. Wound care is also a rising economic problem with an estimated $10 billion annually spent on wound care for older adults. The various causes for delayed healing of aging ultimately result in perturbations of normal wound healing processes. This includes a recently discovered wound healing response incorporating cellular senescence, a biologically active state of permanent growth arrest caused by various stressors like tissue injury. Senescent cells (SnC) that arise acutely in cutaneous wounds have beneficial effects in wound healing when they are transiently present, however, specific SnC identities and their associated functions during wound healing have still not been thoroughly characterized. My preliminary data generated during my GEMSSTAR award confirm a robust and transient increase in beneficial senescence during excisional wound healing in young (2 month) mice, required for timely wound resolution. However, my data also demonstrates that in aged (24 month) mice with delayed wound healing, this acute wound senescence response is significantly attenuated. A similar diminished acute senescence-like response occurs during aged human wound healing suggesting that attenuation is conserved between species. To gain better understanding of wound SnCs that benefit wound healing and which are diminished in aging, my lab has isolated high-expressing p16Ink4a (a common senescence marker) cells from the wounds of young p16tdTom mice. Preliminary single-cell RNAseq analysis reveals multiple wound cell types with high p16+ expression during wound healing. A majority are within distinct clusters of fibroblasts (Fb) and macrophages (Mϕ) with p16+ expression associated with positive regulation of wound healing: p16+ wound Fbs upregulate genes for protein synthesis and certain collagens while p16+ wound Mϕs are more anti-inflammatory and promote extracellular matrix deposition with both cell types being more apoptosis-resistant compared to their respective p16-negative counterparts. As transient senescence is important for optimal wound healing in younger organisms this project’s goals are to uncover the cellular mechanisms by which specific wound SnCs positively influence wound healing and determine their roles in delayed healing of aging. I will test the overall hypothesis that age-related attenuation of beneficial wound SnCs contributes to delayed wound healing in aged mammals and that restoration of these key wound SnCs can promote more timely wound resolution. The following Aims are designed to elucidate changes in wound SnCs throughout aging, define their beneficial impact on wound healing, and provide the therapeutic framework for treatment of delayed healing of aging with senescence modification.

伤口愈合受损或延迟是主要影响老年人的主要问题