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SCF Complexes: Key to Understanding Cochlear Homeostasis

SCF 复合物：了解耳蜗稳态的关键

基本信息

批准号：
6984126
负责人：
ISOLDE THALMANN
金额：
$ 51.22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-01 至 2007-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6984126
关键词：
HeLa cells acid aminoacid ligase cell cell interaction cell population study cochlea epithelium gap junctions gene deletion mutation guinea pigs laboratory mouse laboratory rat membrane channels organ of Corti protein protein interaction transcription factor ubiquitin

项目摘要

DESCRIPTION (provided by applicant): Terminally differentiated, incapable of dividing, the sensory hair cells of the mammalian auditory organ must last a lifetime. This challenge, daunting in any tissue, is further complicated in the organ of Corti (OC) by the absence of vasculature, a highly positive electrical potential, and the continuous "silent" K+ current. In this setting, even transient departures from the physiological norm result in hair cell death and consequent hearing loss. Ironically, the gene most commonly linked to hereditary deafness disorders (connexin 26, Cx26) is not expressed in the sensory cell, but rather in the supporting cell population, or epithelial support complex (ESC). Two common features unite the diverse cell types of the ESC - an elaborate epithelial gap-junction system (EGJS) and high-level expression of OCP1 and OCP2. Formed by hexagonal arrays of connexin molecules, gap-junctions facilitate movement of low molecular weight compounds - nutrients, metabolites, signaling molecules - between adjacent cells. As the severity of the Cx26 phenotype illustrates, disruption of this transport system has disastrous implications for sensory cell survival. Compelling preliminary evidence links OCP1 and OCP2 to regulation of the EGJS. The two most abundant proteins in the OC, OCP1 and OCP2 display homology to subunits of SCF E3 ubiquitin ligases. These multi-component, multi-functional complexes regulate a broad spectrum of biological processes, typically by targeting critical proteins for ubiquitination. Depending on the precise molecular details of the ubiquitin signal, the modified protein will experience one of several potential fates, including proteolytic destruction or sub-cellular relocation. The coincidence of OCP1-OCP2 expression with the boundaries of the EGJS suggests that the OCP1-OCP2 complex may participate in the ubiquitination of one or more connexin isoforms. This hypothesis is bolstered by the recent demonstration that OCP1 binds to Cx2.6 in vitro. The objective of the proposed research is to examine the functional significance of the OCP1-OCP2 complex and, in particular, its interrelationship with the EGJS. The multi-disciplinary project includes targeted disruption of the OCP1 gene, identification of additional OCP1 target proteins, and biochemical/biophysical characterization of the OCP1-OCP2 complex and OCPl-target complexes. This work will furnish insight into the physiological processes underlying preservation of hair cell function. It will advance our understanding of the system (Cx26) most commonly responsible for congenital hereditary hearing loss. Ultimately, the data from this project could provide a foundation for genetic and pharmacologic intervention in hearing disorders.

描述（申请人提供）：哺乳动物听觉器官的感觉毛细胞终末分化，不能分裂，必须持续一生。这一挑战在任何组织中都是令人生畏的，在Corti器官（OC）中由于缺乏脉管系统、高度正电位和连续的“沉默”K+电流而进一步复杂化。在这种情况下，即使是短暂的偏离生理标准也会导致毛细胞死亡和随之而来的听力损失。具有讽刺意味的是，最常与遗传性耳聋疾病相关的基因（连接蛋白26，Cx 26）不在感觉细胞中表达，而是在支持细胞群或上皮支持复合体（ESC）中表达。ESC的两个共同特征将多种细胞类型结合在一起-精细的上皮间隙连接系统（EGJS）和OCP 1和OCP 2的高水平表达。间隙连接由连接蛋白分子的六边形阵列形成，促进低分子量化合物-营养物质，代谢物，信号分子-在相邻细胞之间的移动。Cx 26表型的严重性表明，这种运输系统的破坏对感觉细胞的存活具有灾难性的影响。令人信服的初步证据将OCP 1和OCP 2与EGJS的调节联系起来。OC中最丰富的两种蛋白质OCP 1和OCP 2与SCF E3泛素连接酶的亚基具有同源性。这些多组分、多功能复合物通常通过靶向关键蛋白质进行遍在化来调节广泛的生物过程。根据泛素信号的精确分子细节，修饰的蛋白质将经历几种潜在的命运之一，包括蛋白水解破坏或亚细胞迁移。OCP 1-OCP 2表达与EGJS边界的重合表明OCP 1-OCP 2复合物可能参与一种或多种连接蛋白亚型的泛素化。这一假设得到了最近OCP 1在体外与Cx2.6结合的证明的支持。这项研究的目的是研究OCP 1-OCP 2复合物的功能意义，特别是它与EGJS的相互关系。该多学科项目包括OCP 1基因的靶向破坏，其他OCP 1靶蛋白的鉴定，以及OCP 1-OCP 2复合物和OCP 1-靶复合物的生化/生物物理表征。这项工作将提供深入了解的生理过程的保护毛细胞的功能。它将促进我们对最常见的先天性遗传性听力损失的系统（Cx 26）的理解。最终，该项目的数据可以为听力障碍的遗传和药物干预提供基础。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Toward an understanding of cochlear homeostasis: the impact of location and the role of OCP1 and OCP2.

了解耳蜗稳态：位置的影响以及 OCP1 和 OCP2 的作用。

DOI：
10.1080/0036554021000028100
发表时间：
2003
期刊：
Acta oto-laryngologica
影响因子：
1.4
作者：
Thalmann,Ruediger;Henzl,MichaelT;Killick,Richard;Ignatova,ElenaG;Thalmann,Isolde
通讯作者：
Thalmann,Isolde

Proteomics and the inner ear.

蛋白质组学和内耳。