Role of c-Mpl in HIV-1 Induced Cytopenias

描述（由申请人提供）：HIV-1感染和HAART可导致血细胞减少，影响感染患者的血细胞形成和免疫应答。PI将利用移植人胎胸腺和肝组织的SCID小鼠（SCID-hu Thy/Liv）研究HIV-1和HAART诱导的多谱系造血抑制机制，并检测细胞因子和药物治疗。 由于血小板生成素（TPO）及其受体（c-mpl）是多系造血的重要效应因子，PI将把这项研究调查的重点放在造血细胞因子上。 c-mpl主要与CD 34+细胞向巨核细胞的分化有关。该提案的具体目标如下：（1）确定在存在或不存在HAART的情况下从HIV-1感染的SCID-hu小鼠获得的CD 34 + c-mpl+细胞相对于CD 34 +c-mpl-细胞在SCID-hu受体的Thy/Liv植入物中重新移植和重建这些CD 34+细胞亚群后的造血恢复效果，（2）确定细胞因子治疗和HAART对CD 34 +c-mpl+细胞与CD 34 +c-mpl-细胞的c-mpl表达和造血恢复效果的影响，和（3）确定用携带人c-mpl基因的慢病毒载体转导的CD 34+细胞是否植入SCID-hu Thy/Thy细胞中，Liv植入和细胞因子治疗将有助于HIV-1感染的多谱系造血。

DESCRIPTION (provided by applicant): HIV-1 infection and HAART can lead to cytopenias affecting blood cell formation and immune responses in infected patients. The PI will utilize the SCID mouse transplanted with human fetal thymus and liver tissues (SCID-hu Thy/Liv) to study the mechanisms of HIV-1 and HAART induced multilineage hematopoietic inhibition and testing cytokines and drug therapies. The PI will focus this research investigation on the hematopoietic cytokine, thrombopoietin (Tpo) and its receptor (c-mpl) since they are important effectors of multilineage hematopoiesis. The c-mpl is primarily associated with differentiation of CD34+ cells into megakaryocytes. The Specific aims of the proposal are as following: (1) to determine hematopoietic revival effects of CD34+c-mpl+ versus CD34+c-mpl- cells obtained from HIV-1 infected SCID-hu mouse in the presence or absence of HAART, following re-engraftment and reconstitution of these CD34+ cell subsets in the Thy/Liv implants of SCID-hu recipients, (2) to determine the effects of cytokine treatment and HAART on the c-mpl expression and hematopoietic revival effects of CD34+c-mpl+ versus CD34+c-mpl- cells, and (3) to determine if engraftment of CD34+ cells transduced with a lentiviral vector carrying human c-mpl gene into the SCID-hu Thy/Liv implants and cytokine treatment will contribute to multilineage hematopoiesis in HIV-1 infection.