RNA-binding proteins in atherosclerosis

动脉粥样硬化中的 RNA 结合蛋白

• 批准号: 10375500
• 负责人: Tamer Sallam
• 金额: $ 38.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375500
• 关键词: ATAC-seq; Adenovirus Vector; Affect; Affinity; Architecture; Atherosclerosis; Binding; Binding Proteins; Binding Sites; Biological Assay; Biology; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; ChIP-seq; Cholesterol; Cholesterol Homeostasis; Chromatin; Chromosomes; Chronic; Code; DNA-Binding Proteins; Data; Development; Diagnostic; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Hepatic; Homeostasis; Human; Individual; Lipids; Liver; Liver X Receptor; Location; Maintenance; Mammalian Cell; Maps; Mediator of activation protein; Metabolic; Metabolic Control; Metabolism; Molecular; Mus; Nucleosomes; Nucleotides; Output; Pathway interactions; Pattern; Physiological; Play; Property; Public Health; RNA Binding; RNA-Binding Proteins; Regulation; Regulatory Element; Resolution; Response Elements; Role; Serum; Signal Transduction; Site; Sterol Biosynthesis Pathway; Sterols; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcription Coactivator; Transcription Repressor; Transcriptional Regulation; Untranslated RNA; Work; Yang; Yin; atherogenesis; cholesterol biosynthesis; comorbidity; fatty acid biosynthesis; genome-wide; insight; knock-down; lipid metabolism; loss of function; novel; promoter; sterol homeostasis; transcription factor; uptake

PROJECT SUMMARY/ABSTRACT Perturbations in cholesterol homeostasis are major contributors to cardiovascular disease and associated comorbidities. The objective of this proposal is to define the role of RNA-binding proteins in cholesterol metabolism and atherosclerosis. Interactions between RNA-binding proteins and non-coding RNAs may affect transcriptional outputs at specific genetic zip codes, either locally or across multiple chromosomes. Reinforcing this premise, our preliminary studies suggest that the transcriptional coactivator and RNA-binding protein Raly interacts with the noncoding RNA LeXis to modulate the expression of cholesterol biosynthetic genes. Capitalizing on this novel insight, we aim to investigate the contributions of RALY in sterol metabolism. In Aim 1, we define the physiologic role of Raly in cholesterol metabolism and contributions to atherosclerosis development. We will test out hypotheses by studying mice with tissue specific deletion of Raly or mice transduced with gain- or loss-of-function adenoviral vectors. In Aim 2, we will investigate the mechanisms by which RALY influences gene expression. Utilizing unbiased genome wide approaches will map potential Raly binding sites, its influence on chromatin architecture and decipher its cooperative and hierarchical relationship with transcriptional modulators. These studies are expected to shed fundamental insight into mechanisms controlling metabolic regulation while exploring novel opportunities for therapeutic intervention.

项目概要/摘要 胆固醇稳态的扰动是心血管疾病和相关疾病的主要原因 合并症。该提案的目的是确定 RNA 结合蛋白在胆固醇中的作用 新陈代谢和动脉粥样硬化。 RNA 结合蛋白和非编码 RNA 之间的相互作用可能会影响 特定遗传邮政编码的转录输出，无论是本地的还是跨多个染色体的。 我们的初步研究表明转录共激活因子和 RNA 结合强化了这一前提 Raly 蛋白与非编码 RNA LeXis 相互作用，调节胆固醇生物合成的表达 基因。利用这一新颖的见解，我们旨在研究 RALY 在甾醇代谢中的贡献。 在目标 1 中，我们定义了 Raly 在胆固醇代谢中的生理作用以及对动脉粥样硬化的贡献 发展。我们将通过研究 Raly 组织特异性缺失的小鼠或小鼠来检验假设 用获得或丧失功能的腺病毒载体转导。在目标 2 中，我们将通过以下方式研究其机制： RALY 影响基因表达。利用无偏见的全基因组方法将绘制潜在的 Raly 结合位点，其对染色质结构的影响并破译其合作和层次关系 与转录调节剂。这些研究有望提供对机制的基本见解 控制代谢调节，同时探索治疗干预的新机会。

项目成果

Liver X Receptor Nuclear Receptors Are Transcriptional Regulators of Dendritic Cell Chemotaxis.

肝脏 X 受体核受体是树突状细胞趋化性的转录调节因子。

• 发表时间: 2018
• 影响因子: 5.3
• 作者: Beceiro, Susana;Pap, Attila;Czimmerer, Zsolt;Sallam, Tamer;Guillén, Jose A;Gallardo, Germán;Hong, Cynthia;A;Tabraue, Carlos;Diaz, Mercedes;Lopez, Feli;Matalonga, Jonathan;Valledor, Annabel F;Dominguez, Pilar;Ardavin, Carlos
• 通讯作者: Ardavin, Carlos

LncRNAs in Inflammation: Lessons From a Preclinical Investigation of Mexis Therapy in Atherosclerosis.

炎症中的 LncRNA：Mexis 疗法治疗动脉粥样硬化临床前研究的经验教训。

• 发表时间: 2022-09
• 作者: Salisbury, David A;Kallapur, Aneesh;Repetti, Giuliana G;Fraga, Josue;Kim, Jason;Wu, Xiaohui;Sallam, Tamer
• 通讯作者: Sallam, Tamer

Long Non-coding RNAs in Atherosclerosis: JACC Review Topic of the Week

动脉粥样硬化中的长非编码 RNA：JACC 本周评论主题

• 发表时间: 2024-09-13
• 作者: Zhengyi Zhang;David A. Salisbury;T. Sallam
• 通讯作者: T. Sallam

Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy.

糖尿病血管病变中内皮细胞 LEENE 对非编码 RNA 的影响。

• 发表时间: 2023-02-01
• 作者: Kallapur, Aneesh;Sallam, Tamer
• 通讯作者: Sallam, Tamer

A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.

PPARγ/长非编码RNA 轴调节小鼠脂肪热中性重塑。

• 发表时间: 2023-11-01
• 作者: Zhang, Zhengyi;Cui, Ya;Su, Vivien;Wang, Dan;Tol, Marcus J;Cheng, Lijing;Wu, Xiaohui;Kim, Jason;Rajbhandari, Prashant;Zhang, Sicheng;Li, Wei;Tontonoz, Peter;Villanueva, Claudio J;Sallam, Tamer
• 通讯作者: Sallam, Tamer