Motor Protein Dynamics and Mitotic Mechanisms

描述（由申请人提供）：我们基因组的稳定繁殖需要精确分离复制的染色体，并将一个细胞适当地分裂成两个子细胞。这些过程取决于后期开始前形成双极纺锤体和后期开始后形成中心纺锤体（或中间区）。我们的长期目标是研究这些复杂和动态的微管结构是如何组装和运作的。为了实现这一目标，我们提出了一种跨学科的方法，重点研究细胞分裂所需的进化保守蛋白激酶-5和polo样激酶（Plks）。Eg5（脊椎动物运动蛋白- 5）和Plks的化学抑制剂正在被评估为癌症治疗的药物。我们的研究将深入了解这些蛋白质的细胞分裂功能，并影响针对它们的药物的开发。在这个项目中，我们将：(i)检查两个微管之间单个Eg5分子的运动，（ii）表征Eg5的结构组织如何影响其运动特性和功能，（iii）检查polo样激酶在细胞分裂过程中调节微管动力学中的作用，（iv）表征在细胞分裂过程中调节微管动力学的polo样激酶底物，(v)检查polo样激酶在启动细胞分裂中的作用。细胞分裂中的错误与人类的发育缺陷和疾病有关。我们的研究将提供深入了解的机制，确保这一基本细胞过程的保真度。该申请是根据通知号（no - od -09-058，标题：NIH宣布竞争性修订申请的恢复法案基金的可用性）提交的。

DESCRIPTION (provided by applicant): The stable propagation of our genomes requires the accurate segregation of replicated chromosomes and the proper cleavage of a cell into two daughters. These processes depend on the formation a bipolar spindle before anaphase and a central spindle (or midzone) once anaphase starts. Our long-term goal is to examine how these complex and dynamic microtubule-based structures assemble and function. As steps to achieving this goal, we propose an interdisciplinary approach, focusing on kinesin-5 and Polo-like kinases (Plks), evolutionarily conserved proteins required for cell division. Chemical inhibitors for Eg5 (the vertebrate kinesin- 5) and Plks are being evaluated as drugs for cancer therapy. Our studies will provide insight into the cell division functions of these proteins and also impact the development of drugs that target them. In this project we will: (i) Examine the motility of single Eg5 molecules between two microtubules, (ii) Characterize how Eg5's structural organization influences its motile properties and function, (iii) Examine the role of Polo-like kinases in regulating microtubule dynamics during cell division, (iv) Characterize Polo-like kinase substrates that regulate microtubule dynamics in dividing cells, (v) Examine the role of Polo-like kinases in initiating cytokinesis. Errors in cell division have been linked to developmental defects and diseases in humans. Our studies will provide insight into the mechanisms that ensure the fidelity of this basic cellular process. The application is submitted in response to Notice Number (NOT-OD-09-058, Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications). PUBLIC HEALTH RELEVANCE: Errors in cell division are linked to developed defects and disease in humans. Our project focuses on examining molecular mechanisms that ensure the fidelity of cell division and has the potential to impact therapeutic strategies based on targeting cell division.