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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，慢性不愈性溃疡影响着超过 650 万人，其中主要是老年人。老化是这是大多数慢性疾病的主要风险因素，导致发病率、死亡率和医疗费用。它可能通过针对衰老机制（例如细胞）来延缓与年龄相关的疾病作为一个整体是可行的衰老。事实上，伤口愈合中的衰老表现出一种与环境相关的作用，即持久性慢性伤口床中的衰老表现是有害的。我们发现衰老相关基因人类糖尿病足溃疡中蛋白质-蛋白质相互作用网络上调，这可以表现为尽管有标准护理，但仍需要数月至数年。这与细胞衰老发挥作用的教条相反对急性伤口愈合有有益作用。为了重现慢性伤口床，我们建立了氧化应激诱导的小鼠慢性伤口模型，在真皮组织中表现出更高的衰老负担，导致伤口愈合延迟。我们的假设是局部药理学靶向生存衰老细胞中的通路可以改善慢性伤口愈合。开发化合物至关重要选择性靶向衰老细胞——senolytic 药物。我们策划了临床级局部 senolytic 原型在体外和体内选择性消除衰老细胞的药物。目标 1 是定义特定的衰老细胞慢性伤口床的类型。我们将剖析衰老细胞的生存和累积机制伤口慢性化。我们发现人类糖尿病性溃疡的以下区域存在更高水平的细胞衰老真皮纤维化。因此，我们怀疑存在有感觉的细胞亚型，特别是衰老的成纤维细胞，导致不良表型。我们将利用我们的发现，即由不同细胞产生的衰老细胞不同类型对不同衰老抑制剂的敏感性不同，以发现细胞类型特异性的衰老途径。目标2 目的是测试口服 senolytic 制剂与外用 senolytic 制剂在清除慢性伤口方面的有效性体内衰老细胞。我们将评估氧化应激诱导的慢性伤口中衰老细胞的清除情况 INKATTAC 小鼠的床。将测试抗衰老药物及其组合对衰老表型和衰老表型的影响在与慢性伤口相关的模型中。针对消除衰老细胞的新策略可能会导致治疗老年人慢性不愈合溃疡的转变。