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一个主要影响老年人的主要问题，在 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，导致严重的发病率和死亡率。伤口护理也在兴起 经济问题，估计每年花费100亿美元用于老年人的伤口护理。各种不同的 衰老延迟愈合的原因最终会扰乱正常的伤口愈合过程。这 包括最近发现的伤口愈合反应，结合了细胞衰老，一种生物活性 由组织损伤等各种压力因素引起的永久性生长停滞状态。出现的衰老细胞(SNC) 皮肤伤口中的尖锐物质在短暂存在时对伤口愈合有有益的影响， 然而，特定的SNC身份及其在伤口愈合过程中的相关功能仍未得到 彻底刻画的。我在GEMSSTAR颁奖期间产生的初步数据证实了 幼年(2个月)小鼠在切除创面愈合过程中有益衰老的暂时性增加 及时解决伤口问题。然而，我的数据也表明，在老年(24个月)小鼠中， 伤口愈合后，这种急性伤口衰老反应明显减弱。类似的消退的急性 在人体老年伤口愈合过程中出现类似衰老的反应，这表明衰减是保守的 在物种之间。为了更好地了解有利于伤口愈合的伤口SNC，以及哪些是 在衰老过程中，我的实验室已经分离出高表达的p16INK4a(一种常见的衰老标志物)细胞 P16tdTom幼鼠的伤口。初步单细胞RNAseq分析显示多种创伤细胞类型 在伤口愈合过程中p16+高表达。大多数位于不同的成纤维细胞簇(FB)和 表达p16+的巨噬细胞(M-ϕ)与创伤愈合的正向调节相关：p16+创伤FBS 上调蛋白质合成和某些胶原蛋白的基因而p16+创伤MϕS更具抗炎作用 并促进细胞外基质沉积，与其相比，这两种细胞类型具有更强的抗凋亡能力 各自的p16阴性对照。因为短暂的衰老对创面的最佳愈合很重要 较年轻的生物体该项目的目标是揭示特定损伤SNCs的细胞机制 对伤口愈合有积极影响，并确定其在衰老延迟愈合中的作用。我会测试一下整体的 增龄相关的有益创面SNCs的减弱是老年人创面延迟愈合的原因 哺乳动物和这些关键伤口SNCs的修复可以促进更及时的伤口愈合。这个 以下目的旨在阐明创伤SNCs在衰老过程中的变化，确定它们的有益影响 为治疗衰老延迟愈合提供了治疗框架。 衰老修饰。