Regulation of Spindle Positioning

主轴定位调节

• 批准号: 9080165
• 负责人: Steven M Markus
• 金额: $ 29.43万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9080165
• 关键词: Adaptor Signaling Protein; Affect; Animal Model; Applications Grants; Binding; Biological; Biological Models; Biological Process; Cardiac; Cell Nucleus; Cell division; Cell physiology; Cells; Collaborations; Complex; Cytokinesis; Defect; Development; Developmental Process; Dynein ATPase; Effector Cell; Ensure; Event; Future; Genetic; Geometry; Goals; Health; Histocompatibility Testing; Homeostasis; Homologous Gene; Human; Image; In Vitro; LIS1 protein; Laboratories; Lead; Life; Light; Link; Maintenance; Malignant Neoplasms; Mediating; Microtubules; Minus End of the Microtubule; Mitotic spindle; Molecular; Molecular Motors; Mothers; Motor; Movement; Neck; Organ; Organism; Positioning Attribute; Process; Proteins; Regulation; Research; Role; Saccharomycetales; Site; Stem cells; Testing; Therapeutic Intervention; Time; Tissues; Yeasts; base; biophysical techniques; cancer initiation; cell cortex; cell motility; cell type; daughter cell; developmental disease; dynactin; effective therapy; genetic regulatory protein; human disease; in vivo; insight; lissencephaly; novel; prevent; progenitor; programs; protein purification; public health relevance; receptor; single molecule; stem cell division; tumor progression

 DESCRIPTION (provided by applicant): In many tissue types, cell fate and consequent tissue organization are dictated by the orientation of the mitotic spindle with respect to the cell boundaries. During such processes as organismal development and tissue homeostasis, spindle orientation dictates the plane of cell division, and thus whether a cell divides symmetrically or asymmetrically. Symmetric stem cell divisions result in two identical stem cells, whereas a switch to asymmetric division results in one stem cell and a differentiated cell. Thus, proper coordination of spindle position with the particular needs of a tissue or cell type is critial during numerous biological processes. Improper spindle orientation can compromise asymmetric stem cell divisions, impair differentiation, and lead to defects in tissue development and homeostasis. In fact, unchecked symmetric and asymmetric divisions have both been directly linked to cancer initiation and progression. A key effector of spindle orientation is the molecular motor cytoplasmic dynein. This motor is anchored at the cell cortex from where it orients the spindle through precisely tuned interactions with microtubules. It is unclear how cortically anchored dynein motors perform this function with appropriate directional and temporal control to achieve proper tissue specific functions. The lack of such information presents an impediment towards the development of effective therapies that may prevent or reverse defects in tissue organization that can lead to developmental disorders or cancer. In the proposed studies, we will use the simple model organism budding yeast - in which dynein and many of its regulators are highly conserved - and a combination of in vivo, in vitro, and biophysical methods to determine the mechanisms by which dynein is activated to perform its spindle orientation function, and regulated to achieve appropriate directionally biased spindle movements. Our specific aims are: (1) determine how cortical dynein activity is switched on, and (2) determine how dynein-mediated spindle movements are directionally biased.

 描述（由适用提供）：在许多组织类型中，细胞命运和随之而来的组织组织是由有丝分裂纺锤体相对于细胞边界的方向决定的。在组织发展和组织稳态等过程中，纺锤体取向决定了细胞分裂的平面，因此是对称或不对称的细胞分裂。对称干细胞分裂导致两个相同的干细胞，而切换到不对称分裂会导致一个干细胞和一个分化细胞。在众多生物过程中，纺锤体或细胞类型的特殊需求的适当协调与组织或细胞类型的特殊需求进行了适当的协调。纺锤体方向不当会损害不对称的干细胞分裂，损害分化并导致组织发育和稳态缺陷。实际上，未检查的对称和不对称分裂都与癌症的开始和进展直接相关。主轴取向的关键效应因子是分子运动细胞质动力蛋白。该电动机通过与微管的精确调谐相互作用锚定在细胞皮质上。目前尚不清楚皮质锚定的动力蛋白电动机如何通过适当的定向和临时控制执行此功能，以实现适当的组织特定功能。缺乏此类信息会妨碍开发有效的疗法，这些疗法可能会阻止或逆转组织组织中可能导致发育障碍或癌症的缺陷。在拟议的研究中，我们将使用简单的模型组织萌芽的酵母 - 在该酵母中，动力蛋白及其许多调节剂具有高度保守的酵母菌 - 体内，体外和生物物理方法的组合来确定激活Dynein的机制以执行其纺锤体方向功能，并调节以实现适当的方向性危险的纺锤体运动。我们的具体目的是：（1）确定如何打开皮质动力蛋白活性，（2）确定如何将动力蛋白介导的纺锤体运动偏置。