Regulation of T Cell Activation and Development by PIK3IP1

描述(由申请人提供)：PI-3激酶(PI3K)途径的适当调节对正常T细胞发育、激活和动态平衡至关重要。该途径的几个负调控因子已被广泛描述，其中两个是肿瘤抑制因子。最近，又发现了PI3K途径的另一个负调控因子。PIK3IP1是一种跨膜蛋白，具有结合催化蛋白p110并阻止其激活的能力。到目前为止，关于PIK3IP1在调节淋巴细胞发育或激活中的可能作用尚不清楚。我们发现PIK3IP1在T细胞中表达，并且PIK3IP1的异位表达抑制了TCR/CD28信号的诱导转录。相反，siRNA介导的PIK3IP1沉默增强了相同途径的激活。这些结果表明，PI3K调节因子PIK3IP1在T细胞活化中起重要作用。因此，我们将确定PIK3IP1对TCR和CD28下游特定信号通路的影响，包括PIK3IP1中特定结构域在这一活动中的作用。我们还将检测PIK3IP1消息和蛋白在正常小鼠T细胞发育过程中的表达。最后，我们将鉴定在T细胞谱系中缺乏该蛋白表达的PIK3IP1的可诱导敲除。 公共卫生相关性：该项目的完成将使我们能够首次确定新型蛋白PIK3IP1在T细胞发育和激活中的作用。这些研究可能会为进一步在体内表征PI3K途径的新调节因子在T细胞生物学的正常和病理方面的功能打开大门。鉴于已知PI3K在人类疾病中的作用，这可能包括与各种癌症或自身免疫性疾病的诊断或治疗相关的信息。

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. PUBLIC HEALTH RELEVANCE: Completion of this project will allow us to determine, for the first time, the role of the novel protein PIK3IP1 in T cell development and activation. These studies may open the door to further in vivo characterization of the function of this novel regulator of the PI3k pathway in normal and pathological aspects of T cell biology. Given what is known about the role of PI3k in human disease, this may include information relevant for the diagnosis or treatment of various cancers or autoimmune diseases.