A new biomarker for diabetic foot ulcers

描述(由申请人提供)：本提案是对新的NIDDK公告(PA-14-058)的响应，该公告呼吁开发方法学或生物标记物，以帮助了解T1D 1型糖尿病(T1D)并发症的病理生理学。据估计，在美国2580万糖尿病患者中，有15%-25%的人会在一生中的某个时候患上糖尿病足溃疡(DFU)。DFU是由无法愈合的伤口引起的非创伤性下肢截肢的主要原因。尽管开发了数千种敷料产品来治疗慢性伤口，但没有一种产品被证明对DFU有效。正如RFA所述，糖尿病并发症药物开发进展的一个重要障碍是缺乏用于衡量糖尿病并发症的开始、进展和治疗反应的生物标记物和替代终点。尽管未愈合的DFU涉及多种因素，但组织缺血是导致创面愈合不良的主要因素。缺血可能不是DFU的始动因素，因为大多数溃疡起源于神经病变、压力负荷和/或创伤。然而，组织缺血是阻碍愈合的主要原因。为慢性溃疡提供氧气并没有取得稳定的结果。这是因为氧气只是生产HEP所需的成分之一。这个I期提案的具体目的是探索使用高能磷酸盐(HEP)含量作为预测糖尿病溃疡进展和复发的生物标志物的可能性。我们计划使用糖尿病动物创面模型，在有和没有缺血的情况下，测试HEP在这些创面中的变化，以及几个已知对伤口愈合至关重要的关键因子的表达，并将它们联系起来，初步了解这些因素与糖尿病创面愈合的关系。这一结果可能提供一个初步的迹象，无论是单独的HEP含量的变化，还是与其他关键因素一起使用，将更好地预测愈合的可能性。这是一项困难的工作，但我们已经有了概念验证。

DESCRIPTION (provided by applicant): This proposal is submitted in response to the new NIDDK announcement (PA-14- 058) calling for development of methodologies or biomarkers to help understand the pathophysiology of T1D type 1 diabetes (T1D) complications. An estimated 15-25% of the 25.8 million diabetic patients in this country will develop diabetic foot ulcers (DFU) at some point in their lives. DFU is the leading cause of non-traumatic lower-extremity amputations caused by non-healing wounds. Despite thousands of dressing products developed to treat chronic wounds, none has proven effective for DFU. As stated in the RFA, a significant obstacle for progress in developing drugs for diabetic complications is the paucity of biomarkers and surrogate endpoints for measuring the initiation, progression, and response to treatments of diabetic complications. Although many factors are involved in non-healing DFU, tissue ischemia is known to be a major factor contributing to poor wound healing. Ischemia may not be the initiating factor for DFU, because most ulcers start from a combination of neuropathy, pressure loading, and/or trauma. However, tissue ischemia is the main cause that hinders healing. Providing oxygen to chronic ulcers has not obtained stable results. This is because oxygen is only one of the ingredients required for HEP production. The specific aim of this phase I proposal is to explore the possibility of using high- energy phosphate (HEP) contents as a biomarker to predict the progression and recurrence of diabetic ulcers. We plan to use a diabetic animal wound model, with and without ischemia, to test the changes of HEP in these wounds, along with the expression of several key factors known to be critical to wound healing, such as vascular endothelial growth factors, cytokines, macrophages, collagens, and angiogenesis, and correlated them to obtain a preliminary picture of the relationship between these factors and the haling of diabetic wounds. The result may provide a preliminary indication whether the change of HEP content alone, or along with other key factors, will be better used to predict the likelihood of healing. This is a difficult job, but we already have a proof-of-concept.