Topical Senolytics for Chronic Wound Healing

摘要 在美国，慢性无法愈合的溃疡影响着超过650万人，其中主要是老年人。老龄化是 这是导致发病率、死亡率和医疗费用的大多数慢性病的主要风险因素。它可能 可以通过针对衰老机制，如细胞衰老机制，作为一个群体来延迟与年龄相关的疾病 衰老。事实上，伤口愈合过程中的衰老表现出与环境相关的作用，从而持续 在慢性伤口床上表现出衰老是有害的。我们发现衰老相关基因 而蛋白质-蛋白质相互作用网络在人类糖尿病足部溃疡中上调，这可以在 几个月到几年，尽管有标准的护理。这与细胞衰老扮演着 在急性伤口愈合中的有益作用。为了重述慢性伤口床，我们建立了一种氧化 应激诱导的小鼠皮肤组织衰老负荷较高的慢性创伤模型， 导致伤口愈合延迟。我们的假设是局部药物靶向生存 衰老细胞中的通路可以促进慢性伤口的愈合。至关重要的是要开发出能够 选择性地针对衰老细胞--促衰剂。我们策划了典型的临床级局部感觉剂 在体外和体内选择性地消除衰老细胞的试剂。目标1是定义特定的衰老细胞 慢性创面床的类型。我们将解剖衰老的细胞存活和与 伤口慢性。我们发现，人类糖尿病溃疡在以下区域的细胞衰老水平较高 皮肤纤维化。因此，我们怀疑存在敏感细胞亚型，特别是衰老的成纤维细胞。 会导致不利的表型。我们将利用我们的发现，衰老的细胞来自不同的细胞 不同类型的感受器对不同的感觉剂的敏感性不同，以发现细胞类型特定的感受器裂解途径。目标2 是为了测试口服感觉剂与外用感觉剂在清理慢性伤口方面的效果 体内的衰老细胞。我们将评估氧化应激诱导的慢性创面中衰老细胞的清除情况 在INKATTAC小鼠身上睡觉。将测试增感剂及其组合对衰老表型和 在与慢性创伤有关的模特中。针对消除衰老细胞的新策略可能会导致 老年人群慢性难愈溃疡治疗方法的转变。

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.