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.

伤口愈合受损或延迟是主要影响老年人的一个主要问题，数以百万计的老年人 美国每年都会受到影响。伤口愈合延迟会增加老年患者患慢性伤口的风险， 伤口感染和组织坏死，导致显着的发病率和死亡率。伤口护理也在兴起 每年估计有 100 亿美元用于老年人伤口护理的经济问题。各种 衰老延迟愈合的原因最终会导致正常伤口愈合过程受到干扰。这 包括最近发现的伤口愈合反应，其中包括细胞衰老，一种生物活性物质 由组织损伤等各种应激源引起的永久性生长停滞状态。出现的衰老细胞 (SnC) 急性皮肤伤口短暂存在时对伤口愈合有有益的影响， 然而，SnC 的具体特性及其在伤口愈合过程中的相关功能尚未得到证实。 彻底表征。我在 GEMSSTAR 获奖期间生成的初步数据证实了稳健且 在年轻（2个月）小鼠的切除伤口愈合过程中，有益衰老的短暂增加，需要 以便及时解决伤口。然而，我的数据还表明，在老年（24 个月）的小鼠中，延迟 随着伤口愈合，这种急性伤口衰老反应显着减弱。类似的急性减弱 衰老样反应发生在老年人类伤口愈合过程中，表明衰减是保守的 物种之间。更好地了解有利于伤口愈合的伤口 SnC 随着年龄的增长而减弱，我的实验室分离出了高表达 p16Ink4a（一种常见的衰老标记）细胞 年轻 p16tdTom 小鼠的伤口。初步单细胞 RNAseq 分析揭示多种伤口细胞类型 伤口愈合过程中 p16+ 表达较高。大多数位于不同的成纤维细胞簇 (Fb) 内 具有 p16+ 表达的巨噬细胞 (Mφ) 与伤口愈合的正向调节相关：p16+ 伤口 Fb 上调蛋白质合成和某些胶原蛋白的基因，而 p16+ 伤口 Mφ 更具抗炎作用 并促进细胞外基质沉积，两种细胞类型都比它们的细胞类型更具抗凋亡性 各自的 p16 阴性对应物。由于短暂的衰老对于最佳伤口愈合很重要 该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衰老延迟愈合中的作用。我来测试一下整体 假设有益伤口 SnC 与年龄相关的衰减会导致老年人伤口愈合延迟 哺乳动物并且修复这些关键伤口 SnC 可以促进更及时的伤口愈合。这 以下目标旨在阐明伤口 SnC 在整个老化过程中的变化，确定其有益影响 伤口愈合，并为治疗衰老延迟愈合提供治疗框架 衰老修饰。