GADS REGULATES THE SIGNALING THRESHOLD THROUGH THE T CELL RECEPTOR

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 T细胞库必须足够多样化，以便我们可能遇到的每一种病原体都能被识别并被摧毁。 必须调节这种巨大的多样性，使T细胞不会识别和破坏我们自己的组织，并导致自身免疫性疾病。 广泛的免疫多样性和限制T细胞库以避免自身免疫之间的平衡在阳性和阴性选择过程中被打破。 当发育中的T细胞首先表达成熟的T细胞受体（TCR）复合物时，测试细胞识别自身MHC复合物的能力。 表达以高亲和力结合MHC的TCR的胸腺细胞经由负选择经历凋亡。 相反，不能结合MHC的T细胞通过“忽视死亡”经历凋亡。 只有表达能够以中等亲和力结合MHC的TCR的T细胞被阳性选择并继续成熟。 该研究项目的目标是了解TCR近端信号事件如何调节下游信号通路。 我们假设Gads衔接蛋白通过TCR调节信号传导阈值。 这一假设是基于先前的观察，表明GADS缺陷小鼠在积极和消极选择中存在缺陷。 尽管有这些缺陷，Gads-/-小鼠可以产生成熟的T细胞，表明Gads不是TCR介导的信号传导所必需的。 为了验证我们的假设，我们将确定GADS依赖的信号通路，所需的积极和消极的选择。 然后，我们将确定Gads如何通过TCR调节信号阈值，进而调节下游信号通路。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The T cell repertoire must be sufficiently diverse so that every pathogen we might encounter can be recognized and targeted for destruction. This great diversity must be regulated so that T cells do not recognize and destroy our own tissues and cause autoimmune diseases. The balance between broad immunologic diversity and restriction of the T cell repertoire to avoid autoimmunity is struck during the processes of positive and negative selection. When developing T cells first express a mature T cell receptor (TCR) complex, the cells are tested for their ability to recognize self-MHC complexes. Thymocytes expressing a TCR that binds MHC with high affinity undergo apoptosis via negative selection. Conversely, T cells that are unable to bind MHC undergo apoptosis via "death-by-neglect". Only T cells expressing a TCR that can bind MHC with moderate affinity are positively selected and continue to mature. The goal of this research project is to understand how TCR-proximal signaling events regulate downstream signaling pathways. We hypothesize that the Gads adaptor protein regulates the signaling threshold through the TCR. This hypothesis is based on previous observations showing that Gads-deficient mice have defects in positive and negative selection. Despite these defects, Gads-/- mice can generate mature T cells, indicating that Gads is not required for TCR-mediated signaling. To test our hypothesis, we will identify the Gads-dependent signaling pathways that are required for positive and negative selection. Then, we will determine how Gads regulates the signaling threshold through the TCR and, in turn, regulates the downstream signaling pathways.