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主要问题， 美国每年都受到影响。伤口愈合延迟会增加老年患者慢性伤口的风险， 伤口感染和组织坏死，导致显著的发病率和死亡率。伤口护理也是一个上升 经济问题，估计每年花费100亿美元用于老年人的伤口护理。的各种 老化的延迟愈合的原因最终导致正常伤口愈合过程的扰动。这 包括最近发现的结合细胞衰老的伤口愈合反应， 由各种应激源如组织损伤引起的永久性生长停滞状态。衰老细胞（SnC） 当它们短暂存在时，在皮肤伤口中的急性毒性对伤口愈合具有有益作用， 然而，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被 彻底表征。我在GEMSSTAR奖期间生成的初步数据证实了一个强大的， 年轻（2个月）小鼠切除伤口愈合期间有益衰老的短暂增加，需要 及时解决伤口然而，我的数据也表明，在老年（24个月）小鼠中， 伤口愈合时，这种急性伤口衰老反应显著减弱。一个类似的减少急性 在老年人伤口愈合期间发生衰老样反应，表明衰减是保守的 物种之间。为了更好地了解有利于伤口愈合的伤口SnC， 我的实验室已经分离出高表达p16Ink4a（一种常见的衰老标志物）的细胞， p16tdTom幼鼠的伤口初步单细胞RNAseq分析揭示多种伤口细胞类型 伤口愈合期间p16+表达较高。大多数在成纤维细胞（Fb）的不同簇内， 具有与伤口愈合的正调节相关的p16+表达的巨噬细胞（M β）：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细胞更具抗炎性 并促进细胞外基质沉积，两种细胞类型与它们的 相应的p16阴性对应物。由于短暂的衰老对于创伤的最佳愈合是重要的， 该项目的目标是揭示特定伤口SnCs的细胞机制， 积极影响伤口愈合，并确定其在延迟老化愈合中的作用。我将测试整体 有益伤口SnCs的年龄相关衰减有助于老年人伤口愈合延迟的假设 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解决。的 以下目的旨在阐明伤口SnC在整个老化过程中的变化，确定其有益影响 对伤口愈合，并提供治疗框架，治疗延迟愈合的老化， 衰老修饰