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Intracellular pattern formation

细胞内模式形成

基本信息

批准号：
10398948
负责人：
JACEK GAERTIG
金额：
$ 30.2万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398948
关键词：
Address Alleles Animals Anterior Apical Armadillo Repeat Biochemical CCNE1 gene Calcium-Binding Proteins Calmodulin-Binding Proteins Cell Polarity Cell division Cells Cilia Complex Cues Cytoskeleton Daughter Epithelial Cells Generations Genes Genetic Genetic Models Genetic Screening Goals Image Inner Hair Cells Interphase Joubert syndrome Labyrinth Left Link Maintenance Malaria Maps Modeling Molecular Morphogenesis Mutation Natural regeneration Oral Organelles Orthologous Gene Outcome Parasites Pathway interactions Pattern Pattern Formation Phenocopy Phenotype Phosphotransferases Physiological Plasmodium Population Positioning Attribute Property Proteins Resolution Role Sensory Side Signal Transduction Structure Surface Tertiary Protein Structure Testing Tetrahymena Tetrahymena thermophila Trauma Work airway epithelium analog antagonist causal variant cell type cilium motility kinetosome molecular domain mutant novel polarized cell reverse genetics scaffold tool

项目摘要

PROJECT SUMMARY/ABSTRACT We will investigate how cytoskeletal organelles organize into patterns in the cell. The fields of motile cilia in epithelial cells and the rows of stereocilia in the inner hair cells are examples of physiologically- important organelle patterns. The known pathways do not satisfactorily explain how organelle patterns form. The ciliated protists (ciliates) assemble unusually complex surface (cortical) patterns. Ciliates faithfully duplicate their cortical pattern during cell division and, despite its complexity, the cortical pattern remains nearly invariable in a population. Thus, even subtle deviations from the normal pattern (e.g. due to a mutation or trauma) can be detected and analyzed over many generations. In the genetic model ciliate Tetrahymena thermophila, hundreds of cortical organelles, including cilia, are arranged along the anteroposterior and circumferential (left-right) axes. We recently identified causal mutations in several classical Tetrahymena pattern mutants, in which organelles assemble at incorrect positions. We found that orthologs of the Hippo pathway kinases and cyclin E are critical for patterning on the anteroposterior axis. We identified a strong candidate for Hpo1, a protein that regulates the positions of organelles on the cell’s circumferential axis. The molecular activities through which these pattern-regulating proteins act, and the basis of their restricted cortical localizations, remain unknown. We will explore the molecular composition of the pathways that drive pattern formation in Tetrahymena, study the properties of the pattern-regulating proteins and develop genetic and biochemical screens to systematically unravel the principles of intracellular patterning through unbiased approaches. The overarching goal for Aim 1 is to uncover the molecular circuitry of “early” Hippo signaling that controls the initial positions of organelles that form during cell division on the anteroposterior cell axis in Tetrahymena. Aim 2 will investigate how the “late” Hippo signaling circuit and cyclin E interact (in a mutually antagonistic manner) to induce and maintain cortical structures that form at the division plane. Aim 3 will investigate factors that regulate the circumferential pattern, including Hpo1, a protein that localizes to the right side of the cell.

项目总结/摘要我们将研究细胞骨架细胞器如何组织成细胞内的模式。活动纤毛的区域上皮细胞中的纤毛和内毛细胞中的静纤毛行是生理学上- 重要的细胞器模式。已知的途径不能令人满意地解释细胞器模式 form.纤毛虫原生动物（纤毛虫）组装异常复杂的表面（皮层）模式。纤毛虫在细胞分裂过程中忠实地复制它们的皮层模式，尽管皮层模式很复杂，在种群中几乎是不变的。因此，即使是与正常模式的细微偏差（例如，由于突变或创伤）可以在多代人的时间内检测和分析。在遗传模型中纤毛四膜虫thermophila，数以百计的皮层细胞器，包括纤毛，排列沿着前后和周向（左右）轴。我们最近发现了几个基因突变典型的四膜虫模式突变体，其中细胞器组装在不正确的位置。我们发现 Hippo通路激酶和细胞周期蛋白E的直系同源物对于在前后方向上形成图案至关重要，轴线我们确定了Hpo 1的一个强有力的候选者，Hpo 1是一种调节细胞器位置的蛋白质，细胞的圆周轴。这些模式调节蛋白的分子活动行为，以及他们的限制皮质定位的基础，仍然未知。我们将探索分子组成的途径，驱动模式形成四膜虫，研究的性质，模式调节蛋白质，并开发遗传和生化筛选系统地解开细胞内模式的原则，通过公正的方法。目标1的首要目标是揭示控制细胞器初始位置的“早期”Hippo信号传导的分子电路在四膜虫的前后细胞轴上的细胞分裂过程中形成。目标2将研究如何 “晚期”Hippo信号通路和细胞周期蛋白E相互作用（以相互拮抗的方式），维持在分裂平面形成的皮质结构。目标3将研究调节周向模式，包括Hpo 1，一种定位于细胞右侧的蛋白质。