Topical Senolytics for Chronic Wound Healing

用于慢性伤口愈合的局部 Senolytics

基本信息

批准号：
10725252
负责人：
Saranya Purushothaman Wyles
金额：
$ 32.28万
依托单位：
MAYO CLINIC ROCHESTER
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：
2023-08-15 至 2025-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725252
关键词：
Abbreviations Ablation Acute Affect Aging Apoptosis Area CASP8 gene CDKN2A gene Cell Aging Cells Chronic Chronic Disease Clinical Clinical Trials Dasatinib Dermal Diabetes Mellitus Diabetic Foot Ulcer Disease Elderly Exhibits Fibroblasts Foundations Functional disorder Genes Goals Hand Health Care Costs Human IL8RB gene Immune System Diseases Impaired healing Impaired wound healing In Vitro Intervention Macrophage Medication Management Methods Modeling Morbidity - disease rate Mus Oral Oxidative Stress Induction Papillary Pathologic Pathway interactions Persons Pharmaceutical Preparations Phenotype Play Population Predisposition Quercetin Reagent Resistance Resolution Risk Risk Factors Rodent Model Role Safety Signal Transduction Skin Testing Therapeutic Tissues United States Work Wound models acute wound age related cell type chronic ulcer chronic wound clinically significant diabetic diabetic ulcer diet-induced obesity effectiveness testing efficacy testing fisetin improved in vivo innovation mortality mouse model non-healing wounds novel pharmacologic prevent programs promoter protein protein interaction prototype senescence skin disorder skin fibrosis skin wound small molecule standard of care systemic inflammatory response wound wound bed wound healing

项目摘要

ABSTRACT Chronic non-healing ulcers affect over 6.5 million people, predominantly elderly, in the United States. Aging is a major risk factor for most chronic diseases that account for morbidity, mortality, and health care costs. It may be feasible to delay age-related diseases as a group by targeting aging mechanisms, such as cellular senescence. Indeed, senescence in wound healing exhibits a context-dependent role whereby persistent senescence expression as in a chronic wound bed is detrimental. We found that senescence-associated genes and protein-protein interaction networks are upregulated in human diabetic foot ulcers, which can manifest for months to years despite standard-of-care. This is contrary to the dogma that cellular senescence plays a beneficial role in acute wound healing. To recapitulate the chronic wound bed, we established an oxidative stress-induced chronic wound model in mice that expresses higher senescence burden in dermal tissues, contributing to wound healing delay. Our hypothesis is that topical pharmacological targeting of survival pathways in senescent cells can improve chronic wound healing. It is crucial to develop compounds that selectively target senescent cells –senolytic agents. We curated prototype clinical-grade topical senolytic agents that selectively eliminate senescent cells in vitro and in vivo. Aim 1 is to define specific senescent cell types in chronic wound bed. We will dissect senescent cell surival and accural mechanisms affiliated with wound chronicity. We found that human diabetic ulcers harbor higher levels of cellular senescence in areas of dermal fibrosis. Thus, we suspect there are sensecent cell subtypes, specifically senescent fibroblasts, that contribute to adverse phenotypes. We will leverage our finding that senescent cells arising from different cell types vary in susceptibility to different senolytic agents to discover cell type-specific senolytic pathways. Aim 2 is to test effectiveness of oral senolytic agents versus topical senolytic agents in clearing chronic wound senescent cells in vivo. We will evaluate senescent cell clearance in a oxidative stress-induced chronic wound bed in INKATTAC mice. Effects of senolytic agents and combinations will be tested on aging phenotypes and in models revelant to chronic wound. Targeting new strategies for elimination of senescent cells could lead to a transformation in treating chronic non-healing ulcers in the elderly population.

抽象的在美国，慢性非治疗溃疡影响了超过650万人，主要是老年人。衰老是大多数慢性疾病的主要危险因素是造成发病率，死亡率和医疗保健费用的主要危险因素。可能通过靶向老化机制（例如细胞），可以延迟与年龄有关的疾病作为一组可行的可行感应。确实，伤口愈合中的感受表现出上下文依赖的作用，持续存在慢性伤口床中的感应表达是有害的。我们发现感应相关的基因和蛋白质 - 蛋白质相互作用网络在人类糖尿病足溃疡中进行了更新，这可以表现为几个月至几年的目的地护理标准。这与细胞感应扮演的教条形成鲜明对比在急性伤口愈合中的有益作用。为了概括慢性伤口床，我们建立了一种氧化剂压力诱导的慢性伤口模型在小鼠中表达较高的真皮组织中较高的感应伯嫩，导致伤口愈合延迟。我们的假设是生存的局部药物靶向感觉细胞中的途径可以改善慢性伤口愈合。开发化合物至关重要有选择地靶向感官细胞 - 烯醇化剂。我们策划了原型临床级局部鼻溶剂在体外和体内选择性消除感觉细胞的药物。目标1是定义特定的感觉细胞慢性伤口床类型。我们将剖析感官细胞的监控和与伤口慢性。我们发现，人类糖尿病性溃疡具有更高水平的细胞感应。真皮纤维化。我们怀疑有灵敏的细胞亚型，特别是感觉成纤维细胞，有助于不良表型。我们将利用我们的发现，即来自不同细胞引起的感觉细胞类型的敏感性因不同的鼻溶性剂而异，以发现细胞类型特异性鼻溶性途径。目标2 是在清除慢性伤口方面的口服鼻溶剂与局部鼻溶剂的有效性体内感觉细胞。我们将评估氧化应激诱导的慢性伤口中的感觉细胞清除在Inkattac小鼠中的床。鼻溶剂和组合的影响将在衰老表型和在模型中揭示了慢性增益。针对感官细胞演变的新策略可能导致在老年人群中治疗慢性非治疗溃疡的转变。