A new biomarker for diabetic foot ulcers

描述（由申请人提供）：本提案是为了响应新的NIDDK公告（PA-14- 058）而提交的，该公告呼吁开发方法或生物标志物来帮助理解T1D 1型糖尿病（T1D）并发症的病理生理学。据估计，在这个国家2580万糖尿病患者中，有15-25%的人会在生命的某个阶段患上糖尿病足溃疡（DFU）。DFU是由未愈合的伤口引起的非创伤性下肢截肢的主要原因。尽管开发了数千种治疗慢性伤口的敷料产品，但没有一种被证明对DFU有效。正如RFA所述，糖尿病并发症药物开发的一个重大障碍是缺乏生物标志物和替代终点来衡量糖尿病并发症治疗的开始、进展和反应。虽然许多因素都涉及到无法愈合的DFU，但组织缺血是导致伤口愈合不良的主要因素。缺血可能不是DFU的起始因素，因为大多数溃疡起源于神经病变、压力负荷和/或创伤的结合。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还没有获得稳定的结果。这是因为氧气只是HEP产生所需的成分之一。这项I期研究的具体目的是探索利用高能磷酸盐（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伤口模型，有和没有缺血，测试HEP在这些伤口中的变化，以及几个已知对伤口愈合至关重要的关键因素的表达，如血管内皮生长因子、细胞因子、巨噬细胞、胶原和血管生成，并将它们联系起来，初步了解这些因素与糖尿病伤口愈合之间的关系。该结果可能提供了一个初步的指示，是否单独改变HEP含量，或与其他关键因素一起，将更好地用于预测愈合的可能性。这是一项艰巨的工作，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.