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 糖尿病严重损害组织修复过程，导致慢性不愈合伤口，这代表了 导致下肢截肢的主要原因。糖尿病伤口愈合障碍中血管病理学的作用 （“愈合不足”）已经得到了很好的确立，并且外部机械力在伤口愈合中的作用已经得到了证实。 促进过度瘢痕形成（“过度愈合”）也同样得到了充分研究。然而，通过 这些抵消系统在糖尿病组织内相互作用产生不愈合的皮肤溃疡 彻底检查。在NIH资助的研究的前几年，我们已经做出了重要贡献， 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 在小鼠和人的伤口愈合期间对糖尿病亚群进行单细胞分析的第一项研究， 该研究确定了导致血管形成受损和延迟的特定细胞亚型缺失， 治愈最近，机械反应性成纤维细胞群在驱动过度皮肤瘢痕形成中的作用 和无效的伤口闭合已经在类似的病理状态下进行了检查。为了了解 糖尿病和机械力对细胞群体动力学的影响具有更高的精度，我们已经开发了新的 单细胞技术来识别细胞亚群中的关键扰动。在本提案中，我们将应用这些 新兴的组学技术来表征非愈合糖尿病伤口中细胞群的行为。它 是我们的基本假设，即局部组织机械力有助于细胞生态的破坏， 且减轻这些力可以改善愈合。为了实现这一目标，我们将首先 采用一种新的多重方法进行高通量单细胞测序， 在不同的机械环境下人类糖尿病伤口愈合的人群（具体目标1）。我们 然后将使用动物模型证实人类糖尿病细胞群的变化， 评估皮肤张力对愈合动力学的影响（具体目标2），这将进一步阐明皮肤张力对愈合动力学的功能影响。 这些细胞的作用。最后，我们将使用来自电子健康记录的真实的世界数据（RWD）来评估 旨在抵消机械力的疗法的有效性，以开发临床模型来指导治疗 具体目标（3）。总的来说，这项工作将提高我们对糖尿病伤口生物学的理解， 它与外部机械环境的相互作用，为未来的治疗方法铺平了道路， 还为易于应用的力卸载疗法提供了可推广的临床建议 来指导美国各地创伤中心的治疗决策。本提案中所述的研究 反映了多方面的方法，以转化医学研究，我希望实现在我的前进 作为临床科学家的职业生涯。