探讨胶原凝集素-11在泌尿系统感染中的宿主防御作用及其可能机制

泌尿系统感染(UTI)是常见的感染性疾病，是长期困扰糖尿病、肾移植及尿管留置患者的临床问题。抗生素常用于治疗，但感染反复发作以及耐药菌感染患病率不断上升是临床亟待解决的问题，有必要进一步认识UTI的病理机制,积极从宿主内源性防御机制的角度来探寻新的治疗策略。胶原凝集素-11（CL-11）是新发现的可溶性C型凝集素，肾脏是其主要生成器官之一，其主要生物学功能包括结合细菌，调理吞噬，免疫调控等，与宿主防御机制相关。CL-11在UTI中所起的作用尚未见报道。我们提出：肾脏自身生成的CL-11可能在UTI中发挥重要抗感染作用。本课题将使用全身敲除以及肾脏特异性敲除小鼠来明确CL-11在UTI中所起的保护作用以及肾脏生成CL-11的重要性；将探讨该过程所涉及的细胞、分子机制；并探索给予外源性CL-11是否能有效控制UTI。我们的工作将有助于进一步认识UTI的病理机制，并为后续转化医学研究提供依据。

Urinary tract infections (UTI) caused by uropathogenic E. coli remain among the most common infectious diseases worldwide. They are especially frequent in women, children and the elderly and is a particular problem for the patients with diabetes, renal transplantation and indwelling catheters. UTI are the most common hospital-acquired infections in the developed world, which contribute to high financial burden worldwide. Although antibiotics are available to treat the disease, there remain a number of challenges such as frequent recurrence, persistence of infection and the increasing risk of resistance to antibiotics. For these reasons, it is imperative to improve our understanding of UTI pathogenesis and host defence, and identify novel endogenous defence mechanisms and develop new treatment strategies that could be used to improve current treatment...Collectin 11 (CL-11) is a newly described soluble C-type lectin of innate immunity, has a high-level expression in the kidney. It functions as a pattern recognition receptor that mediates diverse biological processes such as neutralisation of pathogens, opsonophagocytosis, modulation of inflammatory responses and triggering complement activation, thus playing important roles in host defence. The role of CL-11 in UTI is so far unknown, we hypothesise that CL-11, in particular locally produced CL-11 in the kidney, plays fundamental roles in host defence against UTI...In the proposed project, we will: i) further confirm the protective roles of CL-11 in UTI and evaluate the importance of renal production of CL-11 for defence against UTI, using the murine model of ascending UTI, in combination with two CL-11 deficient mouse strains (i.e. global deficient, kidney specific deficient), ii) investigate the involved molecular and cellular mechanism of CL-11 confers protection against UTI, iii) and explore the therapeutic potential of pharmacological administration of CL-11 proteins by local (bladder) or systemic (intravenously) delivery. The successful delivery of the project will, for the first time, demonstrate the role of CL-11 in defence against UTI, unravel potential host defence mechanisms in UTI, and provide supporting information for further translational study.