3’ End Regulation in Nociceptor Plasticity

3â结束伤害感受器可塑性的调节

• 批准号: 10669450
• 负责人: Zachary Campbell
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669450
• 关键词: End; Regulation; Nociceptor; Plasticity

Project Summary/Abstract Poorly managed pain creates an enormous burden on our healthcare system and produces tremendous human suffering. Following an injury, pain is caused by the production of inflammatory cytokines that induce changes in the excitability of nociceptor neurons. A better understanding of molecular mechanisms that facilitate nociceptor plasticity is vital for improved pain treatment. Post-transcriptional gene control has emerged as a dominant theme in pain induced plasticity. We focus on Poly(A) binding proteins (PABPs), a conserved family of 3’ end associated factors that regulate translation initiation and play prominent roles in development and memory. We will determine binding specificities for PABPs present in dorsal root ganglion (DRG) neurons using an unbiased next- generation sequencing approach. This information will be used to generate a novel class of chemically stabilized RNAs called specificity-derived competitive inhibitor oligonucleotides (SPOT-ONs). Unlike genome editing or RNA interference, SPOT-ONs are well tolerated and bypass the need for host-factors as they function as “decoys”. A major advantage of pharmacological inhibition as opposed to targeted gene disruption is the ability to simultaneously impair multiple homologues in a larger gene family. Our preliminary findings indicate that a bi- specific PABP SPOT-ON provides robust anti-hyperalgesic effects in vivo. Based on this finding, we hypothesize that PABPs are crucial mediators of plasticity in nociceptors. We describe preliminary development of SPOT- ONs which reduce protein synthesis in nociceptors and act specifically on poly(A)-mediated mRNA translation (Aim 1). We probe PABP mechanism of action through examination of localized translation and global identification of targets in nociceptors (Aim 2). Finally, we determine how PABP inhibition impacts nociceptor excitability and behavioral responses to injury (Aim 3).

项目总结/文摘

项目成果

Global pairwise RNA interaction landscapes reveal core features of protein recognition.

• DOI: 10.1038/s41467-018-04729-0
• 发表时间: 2018-06-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Zhou Q;Kunder N;De la Paz JA;Lasley AE;Bhat VD;Morcos F;Campbell ZT
• 通讯作者: Campbell ZT

The space between notes: emerging roles for translationally silent ribosomes.

注释之间的空间：翻译无声核糖体的新兴角色。

• DOI: 10.1016/j.tibs.2022.02.003
• 发表时间: 2022-06
• 期刊: TRENDS IN BIOCHEMICAL SCIENCES
• 影响因子: 13.8
• 作者: Smith, Patrick R.;Pandit, Sapna C.;Loerch, Sarah;Campbell, Zachary T.
• 通讯作者: Campbell, Zachary T.

Functionally distinct roles for eEF2K in the control of ribosome availability and p-body abundance.

• DOI: 10.1038/s41467-021-27160-4
• 发表时间: 2021-11-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Smith PR;Loerch S;Kunder N;Stanowick AD;Lou TF;Campbell ZT
• 通讯作者: Campbell ZT

A compendium of validated pain genes.

• DOI: 10.1002/wsbm.1570
• 发表时间: 2022-11
• 期刊: WIREs mechanisms of disease
• 影响因子: 3.1

Bipartite interaction sites differentially modulate RNA-binding affinity of a protein complex essential for germline stem cell self-renewal.

双向相互作用位点差异性地调节生殖干细胞自我更新所必需的蛋白质复合物的RNA结合亲和力。

• DOI: 10.1093/nar/gkab1220
• 发表时间: 2022
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Qiu,Chen;Wine,RobertN;Campbell,ZacharyT;Hall,TraciMTanaka
• 通讯作者: Hall,TraciMTanaka