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Transcriptional control of stress-induced resistance to retinal degeneration

应激诱导的视网膜变性抵抗力的转录控制

基本信息

批准号：
10842755
负责人：
John D Ash
金额：
$ 38.37万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10842755
关键词：
Affect Age related macular degeneration Binding Blindness Cell Death Cells Cessation of life ChIP-seq Cytoprotection Data Data Set Disease Disease Clusterings FGF2 gene Gene Expression Genes Genetic Transcription Gliosis Individual Inflammation Inflammatory Injections Injury Knockout Mice Knowledge LIF gene LIFR gene Lead Light Mediating Methods Microglia Modeling Muller&apos s cell Mus Mutation NF-kappa B Pathologic Persons Photoreceptors Phototransduction Play Publications Publishing Quality of life Regulation Research Resistance Retina Retinal Degeneration Rod Role Signal Transduction Site Sorting Stress Techniques Testing Tissues Transcription Coactivator Transcriptional Activation Transcriptional Regulation Transducers United States Work antagonist biological adaptation to stress cell type cytokine data integration design differential expression inherited retinal degeneration injured migration novel therapeutics promoter receptor response retinal neuron retinal rods single-cell RNA sequencing stress state transcription factor

项目摘要

Abstract: Retinal degenerations are a large cluster of diseases characterized by the irreversible loss of photoreceptors. The death of these cells results in a permanent loss of vision that can have debilitating impacts on an individual's quality of life. Despite the diversity among triggers for retinal degenerations, the mechanisms surrounding photoreceptor death are often similar, suggesting the possibility of developing gene/mutation-independent approaches to reduce blindness from multiple forms of retinal degeneration. We and others have shown that STAT3 is activated in all retinal cells, including photoreceptors and Müller cells during inherited retinal degeneration. Additional work has shown that activation of STAT3 plays an essential role in promoting a wide array of gene expression changes to increase the cell’s capacity to resist cell death. However, despite these impressive findings, little progress has been made in identifying the mechanisms by which STAT3 regulates protection. In this project, we will use state of the art techniques including single-cell RNA-seq and integrating the data with cell-specific ChIP-seq to comprehensively identify all genes and transcriptional networks regulated by STAT3 in retinal Müller cells and rods.

抽象的：视网膜变性是一大类疾病，其特征是视网膜不可逆性丧失。光感受器。这些细胞的死亡会导致视力永久性丧失，从而使人衰弱对个人生活质量的影响。尽管视网膜变性的诱因多种多样，光感受器死亡的机制通常是相似的，这表明发生光感受器死亡的可能性与基因/突变无关的方法可减少多种形式的视网膜变性导致的失明。我们等人表明 STAT3 在所有视网膜细胞中都被激活，包括感光细胞和穆勒细胞在遗传性视网膜变性期间。其他工作表明 STAT3 的激活起着至关重要的作用在促进广泛的基因表达变化以增加细胞抵抗细胞死亡的能力中发挥作用。然而，尽管有这些令人印象深刻的发现，但在确定其机制方面却进展甚微。 STAT3 调节保护。在这个项目中，我们将使用最先进的技术，包括单细胞 RNA-seq 并将数据与细胞特异性 ChIP-seq 相结合，以全面识别所有基因和视网膜 Müller 细胞和视杆细胞中受 STAT3 调节的转录网络。