Understand the metabolic fitness of naïve T cells

项目总结/摘要 自身反应性CD4 + T细胞在自身免疫性疾病的发展中起重要作用， 系统性红斑狼疮（SLE），并经常纠缠在一个刺激环与其他免疫细胞。 引起组织损伤和自身抗原释放的自身抗体导致进一步的假激活， 自身反应性CD4 + T细胞的分化。目前尚不清楚通过什么分子机制异常的自我- 识别可导致T细胞内在控制的丧失。在健康的稳态条件下，巡逻的T细胞 遇到自我肽（自我p）和自我p/MHC相互作用驱动T细胞中的低水平，紧张性信号， 已经在自身免疫的背景下讨论了紧张性信号。在这里，我们将探讨如何补药 T细胞中的信号与T细胞代谢有关。 我们过去的努力产生了一个全新的分子模式， (TCR)由此产生的紧张性信号动态调节静息CD4 + T细胞的幼稚状态。鲁塞 实验室发现了一种新的RasGRP1-mTORC1通路，可能由自身p/MHC-TCR信号触发。的 在幼稚T细胞中的强直Rasgrp1-mTOR信号的功能，其在自身肽/MHC-TCR下游的活性 信号，其对紧张性T细胞代谢的影响，以及这些过程与 自身免疫性疾病是完全未知的。我们在这篇文章中发现并提出的T细胞免疫学， 该提案提供了mTOR信号、细胞代谢和细胞凋亡之间的框架和可能的机制联系。 T细胞的自身反应性。我们和优化，条形码，磷酸流，光谱流，和SCENITH- 技术.我们处于一个非常有利的位置，以帮助候选人取得重大进展，以了解 T细胞自我识别的机制含义以及自我识别（自身反应性）的增加如何导致 改变T细胞的代谢。 多样性补充的拟议研究在这里是在父P01补助金的范围内， 与父P01中的项目4最一致。我们将机械地将自我识别与mTORC1联系起来， 信号，研究紧张性mTOR信号和自身p/MHC相互作用对T细胞代谢的影响， 通过询问mTOR靶mRNA来研究幼稚T细胞的核糖体活性。我们设计了一个 为候选人提供详细的职业规划，以推动其职业发展。鲁塞医生有很好的指导 证书和优秀指导的良好记录。

PROJECT SUMMARY/ABSTRACT Auto-reactive CD4+ T cells play an important role in the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and are often entangled in a stimulatory loop with other immune cells. Autoantibodies that cause tissue damage and release of self-antigens lead to further spurious activation and differentiation of self-reactive CD4+ T cells. It is not known through what molecular mechanisms aberrant self- recognition can cause loss of intrinsic control in T cells. Under healthy homeostatic conditions, patrolling T cells encounter self-peptides (self-p) and self-p/MHC interactions drive low-level, tonic signals in T cells and these tonic signals have been discussed in the context of autoimmunity. Here we will investigate whether how tonic signals in T cells connect to T cell metabolism. Our past efforts generated an entirely new molecular paradigm how self-recognition by the T cell receptor (TCR) and the resultant tonic signals dynamically regulate the naïve state of resting CD4+ T cells. The Roose lab discovered a novel RasGRP1-mTORC1 pathway that is likely triggered by self-p/MHC-TCR signals. The function of tonic Rasgrp1-mTOR signals in naïve T cells, its activity downstream of self-peptide/MHC-TCR signals, its effects on tonic T cell metabolism, and the connections and relevance of these processes to autoimmune diseases are completely unknown. The T cell immunology we discovered and present in this proposal provides a framework and possible mechanistic link between mTOR signals, cell metabolism, and autoreactivity of T cells. We and optimized, barcoding-, phospho-flow-, spectral flow-, and SCENITH- technology. We are in an excellent position to aid the candidate to make significant progress to understand the mechanistic implication of self-recognition by T cells and how increased self-recognition (auto-reactivity) leads to altered metabolism of T cells. The proposed research for the Diversity Supplement here is within the scope of the parent P01 grant and most aligned with Project 4 in the parent P01. We will mechanistically connect self-recognition to mTORC1 signals, investigate the impact of tonic mTOR signals and self-p/MHC interactions on T cell metabolism, and study the ribosome activity of naïve T cells by interrogating mTOR target mRNAs. We have designed a detailed career plan for the candidate to propel her career forward. Dr. Roose has excellent mentoring credentials and a proven track record of outstanding mentoring.