CD98 (4F2 antigen) and Integrin Signaling in Vascular Smooth Muscle Cells.

血管平滑肌细胞中的 CD98（4F2 抗原）和整合素信号传导。

• 批准号: 7608770
• 负责人: Dong Yun Lee
• 金额: $ 1.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608770
• 关键词: Affect; Amino Acid Transporter; Amino Acids; Angioplasty; Atherosclerosis; Binding; Blood Vessels; CD98 Antigens; Cell Communication; Cell Proliferation; Cell surface; Classification; Companions; Development; Disease; Extracellular Matrix; Fibroblasts; Figs - dietary; Integrins; Link; Mediating; Membrane Proteins; Mutagenesis; Mutation; Pathogenesis; Phenotype; Play; Recruitment Activity; Regulation; Relative (related person); Role; Signal Transduction; Smooth Muscle Myocytes; Testing; Tissues; Transmembrane Domain; cell behavior; extracellular; insight; mutant; new therapeutic target; reconstitution; response; restenosis; therapeutic target; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Integrin signaling has been proposed to play a major role in the regulation of vascular smooth muscle cell (VSMC) behaviours. Proliferation of VSMCs requires the expression of CD98hc (4F2hc, SLC3A2), which is a membrane protein that is associated with amino acid transport and integrins. CD98hc is associated with cell proliferation in several different tissues but how CD98hc's functions relate to its role in proliferation has not yet been established. There are several studies that suggest a central role of integrins in CD98hc's ability to regulate cell proliferation. Furthermore, proliferation of VSMC is regulated through the ECM interaction, which are mainly mediated through integrins. To test whether CD98hc mediates integrin signaling to regulate the proliferation of VSMCs, I propose to first investigate which function of CD98hc regulates the proliferation of VSMCs. I will utilize a linked deletion and reconstitution strategy to characterize the regions of CD98hc that mediates proliferation. Mutants of CD98hc that affect either integrins or amino acid transporters have been identified previously. These mutants will thus enable me to establish the relative roles of the two interactions in VSMC responses. Mutations of the ¿1 integrin that block CD98hc binding have also been previously identified. I will reconstitute ¿1 null VSMCs with these mutants as a companion strategy to examine the role of integrin interactions in VSMC proliferation. Second I will determine the mechanism by which CD98hc regulates integrin-dependent signaling. I will examine the possible role of CD98hc oligomerization in integrin signaling by systematic mutagenesis of the extracellular and transmembrane domains of CD98hc to identify mutants that disrupt oligomerization and examine their effects on integrin signaling in VSMCs and in fibroblasts. As an alternative mechanism, I will test the possibility that CD98hc binds and therefore recruits key signaling intermediates to integrins. These studies will provide fundamental insight into the role of CD98hc in VSMC proliferation which is an important aspect of the pathogenesis of various diseases including atherosclerosis and post-angioplasty restenosis and may therefore represent a therapeutic target. VSMC proliferation contributes to the pathogenesis of many diseases such as atherosclerosis and post- angioplasty restenosis. The development of new therapeutic targets aimed at reducing vascular smooth muscle cell proliferation relies on studies such as this one that investigate the mechanism controlling vascular smooth muscle cell proliferation.

描述（由申请人提供）：整合素信号传导已被认为在血管平滑肌细胞（VSMC）行为的调节中发挥重要作用。VSMC 的增殖需要 CD98hc（4F2hc、SLC3A2）的表达，CD98hc 是一种膜蛋白， CD98hc 与氨基酸转运相关，而整合素与多种不同组织中的细胞增殖相关，但 CD98hc 的功能与其在细胞增殖中的作用相关。尚未确定整合素在 CD98hc 调节细胞增殖能力中的核心作用。此外，VSMC 的增殖是通过 ECM 相互作用来调节的，而 ECM 相互作用主要是通过整合素介导的。整合素信号传导调节 VSMC 的增殖，我建议首先研究 CD98hc 的哪个功能调节 VSMC 的增殖，我将利用连锁缺失和。先前已经鉴定了影响整合素或氨基酸转运蛋白的 CD98hc 突变体的重建策略，这些突变体将使我能够确定两种相互作用在 VSMC 突变中的相对作用。 ¿先前也已鉴定出阻止 CD98hc 结合的 1 整合素，我将重新构建 ¿ 1 无效 VSMC 与这些突变体作为研究整合素相互作用在 VSMC 增殖中的作用的伴随策略 其次，我将确定 CD98hc 调节整合素依赖性信号传导的机制，我将通过系统研究 CD98hc 寡聚化在整合素信号传导中的可能作用。 CD98hc 的胞外和跨膜结构域的诱变，以鉴定破坏寡聚化的突变体并检查它们对整合素信号传导的影响作为一种替代机制，我将测试 CD98hc 结合并因此招募关键信号中间体整合素的可能性。这些研究将为了解 CD98hc 增殖的作用提供基础见解，CD98hc 增殖是各种疾病发病机制的重要方面。包括动脉粥样硬化和血管成形术后再狭窄，因此可能是 VSMC 增殖的治疗靶点，有助于许多疾病的发病机制，例如动脉粥样硬化和血管成形术后再狭窄 旨在减少血管平滑肌细胞增殖的新治疗靶点的开发依赖于这项研究控制血管平滑肌细胞增殖的机制。