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起着重要作用，包括肌肉收缩、细胞迁移、囊泡运输和极化生长。两种细胞质肌动蛋白异构体：cyto-和？细胞肌动蛋白普遍表达。尽管由不同的基因编码，这些细胞质肌动蛋白异构体在375个氨基酸残基中只有4个不同；然而，这些微小的序列差异在鸟类和哺乳动物之间是保守的，这表明细胞-和？细胞肌动蛋白具有不同的细胞功能。与这一观点相一致的是，细胞的定位——和？细胞-肌动蛋白差异，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，这表明这种异构体在细胞中起着重要的作用，不能被细胞肌动蛋白填充。尽管在了解行动蛋白如何受其他蛋白质调节方面取得了令人印象深刻的进展，但¿-和？细胞-肌动蛋白仍然知之甚少。这项研究的目标包括阐明细胞和细胞的具体功能。哺乳动物内耳中的细胞-肌动蛋白。初步证据表明？细胞-肌动蛋白缺陷小鼠表现为进行性听力丧失。将产生一个细胞行动蛋白缺乏的小鼠，以便比较细胞和细胞的影响。细胞肌动蛋白缺乏对听觉生理的影响。此外，将通过光镜和电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。该奖学金将通过进一步了解细胞和细胞的独特贡献，为改善公共卫生作出贡献。细胞肌动蛋白对正常细胞生物学的影响。此外，进行性耳聋是由人类基因突变引起的。细胞肌动蛋白9ene与？细胞-肌动蛋白缺陷小鼠，其特征可能会提供洞察这种形式的人类耳聋的病理机制。

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.