Quantitative control of phosphorylation and mechanistic links to immune cell decisions

磷酸化的定量控制和与免疫细胞决策的机制联系

• 批准号: 10668527
• 负责人: Rachel A Gottschalk
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668527
• 关键词: Address; Anti-Inflammatory Agents; Biochemical; Biological Process; Biology; Cell physiology; Cells; Complex; Cues; Data; Disease susceptibility; Event; Excision; Family; Foundations; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Immune; Laboratories; Link; Mission; Modeling; National Institute of General Medical Sciences; Pathology; Phosphorylation; Post-Translational Protein Processing; Predictive Factor; Process; STAT protein; Shapes; Signal Pathway; Signal Transduction; Specificity; Stimulus; Work; cytokine; extracellular; insight; novel therapeutic intervention; programs; response; transcription factor; transcriptomics; transmission process

ABSTRACT Cells integrate distinct stimuli through biochemical signaling pathways to induce the appropriate transcriptional programs. In these signaling-to-transcription networks, the rapid addition and removal of post-translational modifications impact the activity and specificity of transcription factors (TFs) to inform resultant cellular function. Understanding how extracellular cues are linked to gene expression is a fundamental challenge in biology. Existing signaling-to-transcription efforts are often constrained in scope, describing signaling events in detail with little transcriptional insights, or focusing on a few static signaling features while addressing more comprehensive genomic questions. My laboratory is addressing this problem in the context of signal transducers and activators of transcription (STATs), a family of TFs that integrate complex cytokine stimuli to inform a range of pro- to anti-inflammatory immune programs. We propose both data-driven and mechanistic modeling approaches to integrate TF dynamics, global phosphorylation, and transcriptomic data to 1) explore signaling mechanisms that shape stimulus-specific STAT phosphorylation dynamics and functions dependent on these dynamics, and 2) systematically identify phosphorylation events and STAT-cooperating TFs that predict specific gene sets. These efforts to link dynamic signaling to gene expression profiles are a step towards identifying and manipulating the biochemical events required for healthy versus pathology-associated gene expression.

摘要

项目成果

Isoform-specific optical activation of kinase function reveals p38-ERK signaling crosstalk.

• DOI: 10.1039/d2cb00157h
• 发表时间: 2023-10-04
• 期刊: RSC CHEMICAL BIOLOGY
• 影响因子: 4.1
• 作者: Zhou, Wenyuan;Ryan, Amy;Janosko, Chasity P.;Shoger, Karsen E.;Haugh, Jason M.;Gottschalk, Rachel A.;Deiters, Alexander
• 通讯作者: Deiters, Alexander