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

• 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
• 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

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.

受损或延迟的伤口愈合是主要影响老年人的主要问题，成千上万的老年人 美国每年受到影响。延迟伤口愈合会增加老年患者的慢性逻辑逻辑的风险， 伤口感染和组织坏死，导致明显的发病率和死亡率。伤口护理也是一个上升 经济问题，估计每年100亿美元用于老年人的伤口护理。各种 延迟愈合的原因最终导致正常伤口愈合过程的扰动。这 包括最近发现的伤口愈合反应，该反应融合了细胞感应，一种生物学活性 由组织损伤等各种压力源引起的永久性生长停滞状态。出现的衰老细胞（SNC） 皮肤伤口急性对伤口的愈合具有有益的作用，当它们暂时存在时， 但是，特定的SNC身份及其在伤口愈合过程中的相关功能仍然没有 彻底表征。我在Gemsstar奖中生成的初步数据证实了强大的 年轻小鼠（2个月）小鼠的弹性伤口愈合期间有益感应的瞬时增长，需要 及时的伤口分辨率。但是，我的数据还表明，在年龄（24个月）的小鼠中 伤口愈合，这种急性伤口的感应反应显着减弱。类似的急性减弱 感官样反应发生在老年人伤口愈合期间，表明衰减是保守的 物种之间。为了更好地了解赢得伤口愈合的SNC，哪些是 我的实验室在衰老中减少了，从 年轻P16TDTOM小鼠的伤口。初步单细胞RNASEQ分析揭示了多种伤口细胞类型 在伤口愈合过程中具有高P16+表达。大多数在成纤维细胞（FB）和 巨噬细胞（Mϕ），具有与伤口正调控相关的p16+表达：p16+伤口FBS 上调蛋白质合成和某些胶原蛋白的基因，而p16+伤口m ϕ则更具抗炎作用 并促进细胞外基质沉积，两种细胞类型的抗凋亡均具有相比 由于瞬态感应对于最佳伤口愈合很重要 年轻的有机体这个项目的目标是揭示特定伤口SNC的细胞机制 积极影响伤口愈合，并确定其在延迟衰老愈合中的作用。我将测试总体 假设与年龄相关的有益伤口SNC的衰减有助于年龄延迟伤口愈合 哺乳动物和这些关键伤口SNC的恢复可以促进更及时的伤口分辨率。这 以下目标旨在阐明整个衰老的伤口SNC的变化，定义其有益的影响 关于伤口愈合，并提供治疗框架，用于治疗延迟衰老的治疗 衰老修饰。