Role of Cytoplasmic Actin Isoforms in the Inner Ear

描述（由申请人提供）：肌动蛋白是自然界中最丰富的蛋白质之一，在几乎所有细胞功能中发挥重要作用，包括肌肉收缩、细胞迁移、囊泡运输和极化生长。两个细胞质肌动蛋白亚型，细胞和？cyto-actin是普遍表达的。虽然由不同的基因编码，这些细胞质肌动蛋白异构体的变化只有4个375个氨基酸残基，然而，这些小的序列差异是鸟类和哺乳动物之间的保守，这表明细胞-和？细胞肌动蛋白具有独特的细胞功能。与这一想法相一致，细胞定位的细胞-和？细胞肌动蛋白不同，这被认为有助于细胞极化。此外，一些？细胞肌动蛋白突变导致人类进行性耳聋，表明这种亚型的重要细胞作用不能由细胞肌动蛋白填补。虽然在理解肌动蛋白如何被其他蛋白质调节方面已经取得了令人印象深刻的进展，但肌动蛋白和肌动蛋白的不同功能是什么？细胞肌动蛋白仍然知之甚少。该奖学金的目标包括阐明细胞和？哺乳动物内耳中的细胞肌动蛋白。初步证据显示？cyto-actin缺陷小鼠表现出进行性听力丧失。一个细胞肌动蛋白缺陷的小鼠将产生允许的影响比较细胞和？细胞肌动蛋白缺乏对听觉生理的影响此外，将通过光学和电子显微镜分析两种模型中极化内耳细胞的结构和功能，以了解听力变化的细胞机制。该奖学金将有助于改善公共卫生，进一步了解不同的贡献，细胞和？细胞-肌动蛋白到正常细胞生物学。此外，人类基因突变导致的进行性耳聋？cyto-actin 9 ene的表达与细胞的表型有关。cyto-actin缺陷小鼠，其特征将可能提供对这种形式的人类耳聋的病理机制的深入了解。

DESCRIPTION (provided by applicant): Actin is one of the most abundant proteins in nature and plays essential roles in almost every cellular function including muscle contraction, cell migration, vesicle trafficking, and polarized growth. Two cytoplasmic actin isoforms, ¿cyto- and ?cyto-actin, are ubiquitously expressed. Although encoded by separate genes, these cytoplasmic actin isoforms vary at only 4 of 375 amino acid residues; however, these small sequence differences are conserved between birds and mammals, suggesting that ¿cyto-- and ?cyto-actin nave distinct cellular functions. Consistent with this idea, the cellular localization of ¿cyto-- and ?cyto-actin differ, which is thought to contribute to cell polarization. Additionally, some ?cyto-actin mutations lead to progressive deafness in humans, indicating an essential cellular role for this isoform that cannot be filled by ¿cyto-actin. Although impressive gains have been made in understanding how actins are regulated by other proteins, the distinct functions of ¿- and ?cyto--actin remain poorly understood. The goals of this fellowship include elucidating the specific functions of ¿cyto- and ?cyto--actin in the mammalian inner ear. Preliminary evidence suggests that ?cyto--actin deficient mice display progressive hearing loss. A ¿cyto-actin-deficient mouse will be generated to allow for a comparison of the effect ¿cyto- and ?cyto-actin deficiency on auditory physiology. Additionally, the structure and function of polarized inner ear cells in both models will be analyzed by both light and electron microscopy to understand the cellular mechanism underling changes in hearing. This fellowship will contribute to improving public health by furthering understanding of the distinct contributions of ¿cyto- and ?cyto--actin to normal cell biology. Additionally, progressive deafness caused by mutation of the human ?cyto-actin 9ene is Paralleled by the phenotype of the ?cyto--actin deficient mouse, characterization of which will likely provide insight into the pathomechanism of this form of human deafness.