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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.

摘要