免疫球蛋白家族成员PZR在造血中的功能研究

PZR (Protein Zero Related) is a glycoprotein that we identified, isolated, cloned, and named in our earlier studies. It belongs to the immunoglobulin family and is a specific binding protein, regulator, and substrate of protein tyrosine phosphatase SHP2. The extracellular part of PZR contains a single Ig domain, and its intracellular segment has two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that interact specifically with SHP-2. As a key signal transducer and bona-fide proto-oncogene product, SHP2 has been extensively investigated, while studies on PZR lag much behind. To explore physiological role of this important molecule, we have generated transgenic mice expressing PZRX, an intracellular domain-truncated form of PZR, in the hematopoietic system driven by a vav-promoter. The mice developed myeloproliferative neoplasms (MPN)-like phenotypes characterized by bone marrow and spleen hyperplasia as they aged. We believe that PZR has an important role in controlling proliferation, differentiation, migration, and commitment of hematopoietic stem/progenitor cells. In this study, we will prove our hypothesis by thoroughly characterizing the phenotype of the PZRX transgenic mice and studying the effects of PZRX expression on activity and signaling of hematopoietic stem/progenitor cells in vitro and in vivo. We have generated a unique mouse model and other valuable reagents for this study. This study should reveal the important role of PZR in regulating hematopoiesis and its potential pathological implications and further define PZR and SHP-2 as targets for therapeutic interventions.

PZR是我们发现并命名的一种属于免疫球蛋白家族的穿膜蛋白。它的胞外部分包括一个免疫球蛋白结构域，胞内部分有两个可与酪氨酸磷酸酶SHP2特异性结合的免疫受体酪氨酸抑制基序。SHP2是原癌基因，在信号传导中起关键作用。为探索PZR的生理功能，我们在小鼠造血系统中表达了不含有胞内部分的截短型PZR蛋白PZRX。这种小鼠表型出类似人骨髓增生性疾病的症状，随着年龄增长而出现的骨髓和脾脏中髓系细胞增生。我们认为PZR控制造血干细胞与祖细胞的增殖、分化、迁移和定向中起着重要作用。在本研究中，我们将彻底探索PZRX转基因小鼠的表型，从体内和体外两方面来研究PZRX的表达对造血干细胞和祖细胞的活性与细胞信号的影响。我们已经建立了独特的小鼠模型，并拥有该研究所需的关键技术。该研究将会揭示PZR在调节造血功能的重要性和在病理发展中的关键作用，同时提供以PZR与SHP-2相互作用为靶点的靶向治疗的理论基础。

PZR是一种属于免疫球蛋白家族的跨膜蛋白。我们通过生物信息学技术发现它与多种肿瘤的发生发展具有很强的相关性。在本课题中，我们重点研究了PZR在造血系统恶性肿瘤中的作用。为探索PZR的生理功能，我们成功构建了在造血系统中表达截短型PZR蛋白PZRX的小鼠模型，该模型表现出类似人骨髓增生性疾病的症状，随着年龄增长而出现的骨髓和脾脏中髓系细胞增生，我们进一步分析发现PZRX能够引发髓外造血，从而引发脾脏增大。在本研究中，我们探索了PZRX转基因小鼠的表型，从体内和体外两方面来研究PZRX的表达对造血干细胞和祖细胞活性的影响，揭示PZR在造血细胞发育过程中起到的重要作用。另外，我们还通过杂交瘤技术获得PZR的单克隆抗体，这为我们研究PZR在细胞信号传导和造血系统中的作用提供了宝贵的工具。