Regulation of T Cell Activation and Development by PIK3IP1

描述（由申请人提供）：PI-3激酶（PI 3 k）通路的适当调节对于正常T细胞发育、活化和稳态至关重要。该途径的几种负调节因子已得到广泛表征，其中两种是肿瘤抑制因子。最近，另一种PI 3 k通路的负调节剂已经被鉴定。PIK 3 IP 1是一种跨膜蛋白，具有结合催化蛋白p110并阻止其活化的能力。到目前为止，还不知道PIK 3 IP 1在调节淋巴细胞发育或活化中的可能作用。我们已经发现PIK 3 IP 1在T细胞中表达，并且PIK 3 IP 1的异位表达抑制TCR/CD 28信号传导至诱导型转录。相反，siRNA介导的pik 3 ip 1沉默增强了相同途径的激活。这些结果表明，PI 3 k调节剂PIK 3 IP 1在T细胞活化中起重要作用。因此，我们将确定PIK 3 IP 1对TCR和CD 28下游特定信号传导途径的影响，包括PIK 3 IP 1内特定结构域对此活性的作用。我们还将检查正常小鼠中整个T细胞发育过程中PIK 3 IP 1信息和蛋白的表达。最后，我们将表征在T细胞谱系中缺乏蛋白表达的PIK 3 IP 1的诱导性敲除。

DESCRIPTION (provided by applicant): Proper regulation of the PI-3 kinase (PI3k) pathway is critical for normal T cell development, activation and homeostasis. Several negative regulators of this pathway have been extensively characterized, two of which are tumor suppressors. Recently, another negative regulator of the PI3k pathway has been identified. PIK3IP1 is a transmembrane protein that has the ability to bind the catalytic protein p110 and prevent its activation. Thus far, nothing is known about the possible role of PIK3IP1 in the regulation of lymphocyte development or activation. We have found that PIK3IP1 is expressed in T cells and that ectopic expression of PIK3IP1 inhibits TCR/CD28 signaling to inducible transcription. Conversely, siRNA- mediated silencing of pik3ip1 augments activation of the same pathways. These results suggest that the PI3k regulator PIK3IP1 plays an important role in T cell activation. We will therefore determine the effects of PIK3IP1 on specific signaling pathways downstream of the TCR and CD28, including the role of specific domains within PIK3IP1 for this activity. We will also examine the expression of PIK3IP1 message and protein throughout T cell development in normal mice. Finally, we will characterize an inducible knockout of PIK3IP1 lacking expression of the protein in the T cell lineage.