探索重组病毒载体用于治疗人类常染色体显性多囊肾病(ADPKD)方法和作用机制的研究

Autosomal dominant polycystic disease (ADPKD) is one of the most common life-threatening genetic diseases. Although considerable progression has been obtained in our understanding of the disease mechanism, there currently is no effective therapy for patients with this disease in clinical practice. We have recently established an ADPKD mouse model (Vil-Cre;Pkd2f3/f3) which mimics clinical manifestations of human ADPKD patients. In addition, we have also generated a transgenic mouse line (PKD2tg), in which expression of the human PKD2 full-length ORF cDNA is controlled by the CMV IE enhancer and the chicken β-actin promoter (pCAGGS expression vector). This transgenic mouse line rescues all disease phenotypes of the ADPKD mouse model (Vil-Cre;Pkd2f3/f3). This finding lay a fundamental base for applying PKD2 transgene to be a therapeutic reagent for treatment of ADPKD models and patients. We have then recently developed a gene delivery system by which the transgene can be transferred into the renal epithelia by hydrodynamic pelvis injection. Our preliminary data indicate this system can deliver a transgene into renal epithelia and remain its stably expressing. We therefore attempt to use the system to transfer functional PKD2 transgene into renal epithelia by this novel technology. The positive finding will certainly provide a new therapeutic approach toward curing this human genetic disease, for which there currently is no effective treatment in clinic.

虽然针对人类常染色体显性遗传性多囊肾病（ADPKD）分子机制和发病机理方面的研究已经取得相当大的进展，但目前为止在临床上仍然没有有效的治疗方法。本课题组不仅创建了一种能够模拟人类ADPKD疾病表型的Pkd2基因突变小鼠模型，还成功地建立了一种带有人类PKD2转基因小鼠模型。这种PKD2转基因鼠可挽救Pkd2基因敲除鼠的胚胎死亡和囊肿表型。这些前期大量的工作为我们实施ADPKD基因治疗奠定了理论基础。此外，本研究组新近成功地开展了小鼠肾盂逆行性注射的方法，因此我们可通过这一逆行注射的方法将功能性PKD2转基因传送到ADPKD小鼠模型的肾上皮细胞，以达到治疗该疾病的目的。我们的这一具有一定开创性的新治疗方案不仅将为ADPKD的提供了一个新的视角，而且使之有可能成为治疗ADPKD的一种有效的方法，并为人类遗传病的新疗法的研究提供极具价值的理论参考依据。

人类遗传性多囊肾病(PKD)是一种常见的遗传性肾功能紊乱综合症。根据遗传方式不同可分为常染色体显性遗传性多囊肾(Autosomal dominant polycystic kidney disease, ADPKD)和常染色体隐性遗传性多囊肾(Autosomal recessive polycystic kidney disease, ARPKD)。ADPKD的主要临床症状为双侧肾脏形成大量大小不等的圆球形液性囊肿，并且进行性增大，破坏肾脏的结构和功能，最终导致肾功能衰竭。目前临床上除肾脏移植外，尚无公认的可用于ADPKD治疗的有效手段和方法。为了解决ADPKD临床治疗的难点和开创治疗该疾病的新措施，本课题组成功地通过新颖的基因传递技术（即广义上的基因治疗）开展了对ADPKD治疗机制的探索研究。

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