Elucidating the role of mechanical forces in diabetic wound healing

阐明机械力在糖尿病伤口愈合中的作用

• 批准号: 10573042
• 负责人: Michael Januszyk
• 金额: $ 15.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573042
• 关键词: Algorithms; Animal Model; Automobile Driving; Biology; Blood Vessels; Cells; Chronic; Cicatrix; Clinical; Data; Databases; Debridement; Diabetes Mellitus; Diabetic mouse; Ecology; Electronic Health Record; Engineering; Environment; Evaluation; Fibroblasts; Funding; Future; Human; Impaired healing; Impaired wound healing; Impairment; In Vitro; Kinetics; Lower Extremity; Machine Learning; Mechanics; Medical Research; Methodology; Modeling; Modernization; Mus; Outpatients; Pathologic; Pathology; Patients; Population; Population Dynamics; Postdoctoral Fellow; Process; Recommendation; Research; Research Training; Role; Sampling; Scientist; Skin; Splint Device; System; Techniques; Technology; Therapeutic; Time; Tissues; Translating; Treatment Efficacy; United States; United States National Institutes of Health; Visit; Work; Wound models; blood vessel development; career; cell behavior; clinical training; diabetic; diabetic ulcer; diabetic wound healing; diagnostic biomarker; efficacy evaluation; electronic health data; electronic health record system; healing; improved; information model; interest; limb amputation; machine learning method; mechanical force; mouse model; neovascularization; next generation sequencing; non-diabetic; non-healing wounds; novel; predictive modeling; pressure; response; routine care; single cell analysis; single cell sequencing; single-cell RNA sequencing; skin ulcer; stem cells; tissue injury; treatment strategy; wasting; wound; wound care; wound closure; wound environment; wound healing; wound treatment

PROJECT SUMMARY / ABSTRACT Diabetes profoundly impairs the tissue repair process, leading to chronic non-healing wounds, which represent a leading cause of lower limb amputations. The role of vascular pathology in impaired diabetic wound healing (“under healing”) has been well established, and the role of external mechanical forces across wounds in promoting excessive scar formation (“over healing”) is similarly well studied. However, the mechanisms through which these countervailing systems interact within diabetic tissue to yield non-healing skin ulcers have yet to be thoroughly examined. During prior years of NIH-funded research, important contributions have been made to our knowledge of the critical role of vascular progenitor cells in normal and diabetic wound healing. These include the first studies on single cell analysis of diabetic subpopulations during wound healing in both mice and humans, which identified specific cell subtype depletions that contribute to impaired blood vessel formation and delayed healing. More recently, the role of mechanoresponsive fibroblast populations in driving excessive skin scarring and ineffective wound closure has been examined in similar pathologic states. To understand the effects of diabetes and mechanical force on cell population dynamics with greater precision, we have developed novel single cell techniques to identify critical perturbations in cell subpopulations. In this proposal, we will apply these emerging -omics technologies to characterize the behavior of cell populations in non-healing diabetic wounds. It is our fundamental hypothesis that local tissue mechanical forces contribute to the disruption of cellular ecology in diabetic wound healing and that mitigation of these forces can improve healing. To achieve this, we will first employ a novel multiplex approach to high-throughput single cell sequencing to evaluate changes to cell populations in human diabetic wounds healing under different mechanical environments (Specific Aim 1). We will then confirm the changes in human diabetic cell populations using animal models, while more precisely assessing the effect of skin tension on healing kinetics (Specific Aim 2), which will further clarify the functional role of these cells. Finally, we will use real world data (RWD) from electronic health records to evaluate the efficacy of therapies aimed at offsetting mechanical forces, in order to develop clinical models to guide treatment strategies (Specific Aim 3). Collectively, this work will enhance our understanding of diabetic wound biology and its interaction with the external mechanical environment, paving the way for future therapeutic approaches, while also providing generalizable clinical recommendations for force offloading therapies that can be readily applied to guide treatment decisions at wound centers across the United States. The studies described in this proposal reflect the multi-faceted approach to translational medical research that I hope to achieve moving forward in my career as a clinician scientist.

项目摘要 /摘要 糖尿病严重损害了组织修复过程，导致慢性非治疗伤口，这代表 下肢截肢的主要原因。血管病理学在受损糖尿病伤口愈合中的作用 （“在治愈下”）已经建立了很好的确立，外部机械力在伤口中的作用 促进多余的疤痕形成（“过度愈合”）同样很好地研究了。但是，机制通过 这些反补脚系统在糖尿病组织中相互作用以产生非治疗的皮肤溃疡 彻底检查。在NIH资助研究的前几年，已经为我们做出了重要的贡献 了解血管祖细胞在正常和糖尿病伤口愈合中的关键作用。这些包括 小鼠和人类伤口愈合过程中糖尿病亚群的单细胞分析的首次研究， 它确定了特定的细胞亚型部署，导致血管形成受损并延迟 康复。最近，机械培养的成纤维细胞种群在驱动多余的皮肤疤痕中的作用 在类似的病理状态下已经检查了无效的伤口闭合。了解 糖尿病和机械力对细胞种群动力学的精确度更高，我们开发了新颖的 单细胞技术以识别细胞亚群中的关键扰动。在此提案中，我们将应用这些 新兴的组织技术表征了细胞群体在非治疗糖尿病伤口中的行为。它 我们的基本假设是局部组织机械力有助于细胞生态的破坏 在糖尿病伤口愈合和缓解这些力量可以改善愈合。为了实现这一目标，我们将首先 员工一种新型的多重方法，用于评估细胞变化的高通量单细胞测序 人类糖尿病伤口中的种群在不同的机械环境下愈合（特定目标1）。我们 然后将使用动物模型确认人类糖尿病细胞群体的变化，而更精确 评估皮肤张力对愈合动力学的影响（特定目标2），这将进一步阐明功能 这些细胞的作用。最后，我们将使用电子健康记录中的现实世界数据（RWD）来评估 旨在抵消机械力的疗法的功效，以开发临床模型以指导治疗 策略（特定目标3）。总的来说，这项工作将增强我们对糖尿病伤的生物学的理解和 它与外部机械环境的相互作用，为将来的治疗方法铺平了道路，而 还为可以容易应用的强制卸载疗法提供可概括的临床建议 指导美国各地伤口中心的治疗决定。该提议中描述的研究 反映了我希望在我的中前进的多方面的翻译医学研究方法 作为临床科学家的职业。