Netherton Syndrome: From mechanisms to therapeutics

内瑟顿综合征（NS）是由编码内源性丝氨酸蛋白酶抑制剂LEKTI的SPINK 5基因的基因突变引起的危及生命的常染色体皮肤病。LEKTI缺乏会破坏皮肤中正常的抑制剂/蛋白酶平衡，并导致异常高的表皮蛋白水解活性、异常脱屑和受损的皮肤屏障功能（NS的标志）。我们的研究小组先前已经确定KLK 5和KLK 7是皮肤LEKTI的最重要靶点，并建立了KLK过度活性与NS发病机制之间的因果关系。在目前的提案中，我们的目标是更好地理解KLK 5和KLK 7在NS中的病理生物学作用的分子机制，并评估用特异性KLK抑制剂阻断KLK的治疗益处。首先，我们的目标是广泛分析NS患者队列中KLK 5和KLK 7的活性，并使用蛋白质组学技术来揭示主要受影响的特定蛋白质和途径。NS的分子基础的描绘将提供不可或缺的洞察力的关键事件，驱动NS的发病机制，并将奠定新的治疗策略的发展奠定了基础。接下来，我们建议使用噬菌体展示技术开发KLK 5和KLK 7的抑制剂，并在小鼠异种移植NS模型系统中评估这些抑制剂。综上所述，我们相信这些研究将提供NS病理生理学的全面理解，并将为开发首个基于KLK的内瑟顿综合征靶向治疗奠定基础。

Netherton Syndrome (NS) is a life-threatening autosomal skin disease caused by genetic mutations in the SPINK5 gene, encoding the endogenous serine protease inhibitor LEKTI. LEKTI deficiency disrupts the normal inhibitor/protease balance in the skin and results in abnormally high epidermal proteolytic activity, aberrant desquamation and impaired skinbarrier functions (hallmarks of NS). Our group has previously identified KLK5 and KLK7 as the most important targets of skin LEKTI and has established a causal relationship between KLK over-activity and NS pathogenesis. In the current proposal we aim to better comprehend the molecular mechanism underlying the pathobiological roles of KLK5 and KLK7 in NS and to evaluate the therapeutic benefit of blocking KLKs with specific KLK inhibitors. First, we aim to extensively profile the activity of KLK5 and KLK7 in a cohort of NS patients and use proteomic technologies to uncover the specific proteins and pathways that are predominantly affected. Delineation of the molecular basis of NS will offer indispensable insights into the key events that drive NS pathogenesis and will lay the foundation for the development of novel therapeutic strategies. Next, we propose the development of inhibitors for both KLK5 and KLK7 using phage display technologies and the evaluation of these inhibitors in mouse xenograft NS model systems. Taken together, we believe that these studies will provide a holistic understanding of NS pathophysiology and will set the stage for the development of the first KLK-based targeted therapies for Netherton Syndrome.