Regulation of T Cell Activation and Development by PIK3IP1

PIK3IP1 对 T 细胞激活和发育的调节

• 批准号: 8240206
• 负责人: Lawrence P. Kane
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240206
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adaptor Signaling Protein; Antineoplastic Agents; Autoimmune Diseases; Autoimmunity; Binding; CD28 gene; Cell Lineage; Cellular biology; Data; Development; Diagnosis; Ectopic Expression; Family; Genetic Transcription; Histocompatibility Testing; Homeostasis; Immune; Integral Membrane Protein; Knock-out; Lead; Lipids; Location; Lymphocyte; Lymphocyte Activation; Lymphoma; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Mus; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Proteins; Publishing; Regulation; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Time; Transcription Factor AP-1; Tumor Suppressor Proteins; base; cell type; human disease; in vivo; knock-down; novel; novel strategies; prevent; protein expression; protein function; receptor; tumor

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.

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被广泛表征，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。 公共卫生关系：该项目的完成将使我们能够首次确定新蛋白PIK 3 IP 1在T细胞发育和激活中的作用。这些研究可能会打开大门，进一步在体内表征的功能，这种新的调节PI 3 k通路在正常和病理方面的T细胞生物学。鉴于已知PI 3 k在人类疾病中的作用，这可能包括与诊断或治疗各种癌症或自身免疫性疾病相关的信息。