CALR突变是原发性血小板增多症（ET）的一个主要分子病因，近期研究认为MPL-JAK2-STAT通路介导了ET的发生。然而此机制无法解释CALR突变产生的巨核系增殖过度而粒系数量基本正常这一现象，为此我们认为可能存在新的机制参与CALR突变致ET的过程。经过前期工作我们发现PDGFRβ可能是介导CALR突变致ET发生的一个关键分子。本项目中我们将通过构建两种CALR突变人巨核细胞株模型即CHRF-288和DAMI，观察PDGFRβ活性被抑制前后CALR突变促细胞增殖的变化情况；通过建立条件性敲除PDGFRβ的CALR突变移植小鼠模型，观察PDGFRβ被诱导敲除前后CALR突变致小鼠ET发生的能力；同时利用上述模型初步分析CALR突变体与PDGFRβ之间的相互作用关系；即从细胞和动物两个方面进行PDGFRβ的功能验证。该研究将有助于完善CALR突变致ET的机制认识，同时为精准治疗提供靶点。

Somatic CALR mutations have recently been discovered to be causative alterations in ET. Two recent articles demonstrated that MPL-JAK2-STAT singnal pathway might influence CALR mutants driven ET phenotype. In clinical, the ET patients with CALR mutations show high platelet counts and normal leukocyte counts. However, MPL-JAK2-STAT singnal pathway can not explain this phenomenon, suggesting that unknown molecular mechanism might influence CALR mutants driven ET. Based on our previous studies, we found that PDGFRβ might operate in the process of CALR mutants driven ET. In this study, functional analysis of PDGFRβ will be further performed by vitro and vivo. In details, we will transduct CALR mutants into CHRF-288cell and DAMI cell by lentiviral vector and assess its impact on proliferation of CHRF-288cell and DAMI cell via inhibition of PDGFRβ. We will transduct CALR mutants in murine by lentiviral vector and knock-out PDGFRβ gene to observe whether it can lead to ET in murine models. Collectively, This research is likely to bring an important impact on our understanding of the genetic basis of patients with ET. It also help us to find a potential drug target.