Evolution of Cargo Transport

在空间和时间上精确地运输蜂窝货物对于所有蜂窝中的许多过程都是至关重要的。不同 细胞类型和生物体使用不同的机器进行长途货物运输。例如，哺乳动物 细胞和许多丝状真菌使用基于微管的马达动力蛋白和动力蛋白运输货物，而 酵母菌在肌动蛋白细胞骨架上使用肌球蛋白马达。尽管对细胞的运输和 对于所涉及的马达，人们对类似的运输机制如何适应特定的细胞类型或 有机体。克里斯滕森博士目前的研究调查了规范(机动车驱动)和非规范货物 运输。在这项提案中，她将研究这两种运输方式是如何在不同的生物体中进化的 使用一种创新的方法，其中进化假说直接使用比较细胞生物学进行检验 在真菌和哺乳动物细胞中。运输障碍在神经系统疾病中尤其普遍，例如 老年痴呆症、亨廷顿氏症和肌萎缩侧索硬化症。研究不同类型的细胞如何以不同的方式使用运输机械 直接适用于理解运输缺陷如何导致细胞特有的疾病。 在目标1中，克里斯滕森博士将研究如何在真菌中进化出电动运输的调节器 和人类细胞。在她目前的研究和该奖项的K99阶段，她将研究基因是如何 ‘FHF’蛋白复合体的扩展和功能多样化使Dynein能够结合多种货物 人类细胞。在该奖项的R00阶段，克里斯滕森博士将确定和表征新颖的动力蛋白 使用进化分析和比较细胞生物学的调节器在弧菌和人类细胞中。 在《目标2》中，克里斯滕森博士将研究一种非规范的交通方式，即搭便车。在……里面 搭便车，一件货物附在另一件货物上，并与另一件货物一起运输，以实现移动性。搭便车有 已被证明存在于两种进化分化的丝状真菌中，即尼杜拉曲霉。 和Ustilago Maydis。在该奖项的K99阶段，她将研究 网纹夜蛾中的过氧化物酶体搭便车和确定mRNA搭便车是否在网纹夜蛾中收敛地进化 还有美式蛋黄酱。在这个奖项的R00阶段，她将确定是否在第三个丝状菌中发生搭便车 真菌，阿什比亚棉，一种缺乏基于微管的典型运输的真菌。 克里斯滕森博士的目标是在细胞和细胞的界面上开发一个独立的研究程序 进化生物学。为了实现这一目标，她将参加跨领域的会议，并参加加州大学圣迭戈分校- 赞助和马赛克UE5倡议侧重于实验室管理和向独立过渡。她 将接受她的指导委员会(以下列出的教职员工)和她的主要导师山姆·雷克的指导- 彼得森。这一发展计划与进化生物学培训(与加州大学圣迭戈分校马特·多尔蒂)相结合， 哺乳动物细胞囊泡运输分析(与Susan Ferro-Novick，UCSD)，以及棉铃虫(与Amy 格拉菲特，北卡罗来纳大学教堂山分校)将为她在独立职位上脱颖而出做好准备。

Transporting cellular cargo with spatial and temporal precision is critical for many processes in all cells. Different cell types and organisms use diverse machineries for long-distance cargo transport. For example, mammalian cells and many filamentous fungi transport cargo using the microtubule-based motors dynein and kinesin, while yeast use myosin motors on actin cytoskeleton tracks. Despite a general understanding of cellular transport and the motors involved, little is known about how similar transport machineries are adapted by specific cell types or organisms. Dr. Christensen’s current research investigates canonical (motor-driven) and non-canonical cargo transport. In this proposal, she will investigate how both modes of transport have evolved in different organisms using an innovative approach in which evolutionary hypotheses are directly tested using comparative cell biology in fungal and mammalian cells. Defects in transport are particularly prevalent in neurological disorders such as Alzheimer’s, Huntington’s and ALS. Examining how diverse cell types differently use the transport machinery is directly applicable to understanding how transport defects lead to cell-specific diseases. In Aim 1, Dr. Christensen will investigate how regulators of motor-driven transport have evolved in fungi and human cells. In her current research and the K99 phase of this award, she will investigate how the gene expansion and functional diversification of the ‘FHF’ protein complex allows dynein to bind multiple cargos in human cells. For the R00 phase of this award, Dr. Christensen will identify and characterize novel dynein regulators using evolutionary analysis and comparative cell biology in A. nidulans and human cells. In Aim 2, Dr. Christensen will investigate a non-canonical form of transport known as ‘hitchhiking’. In hitchhiking, a cargo attaches to and is co-transported with another cargo to achieve motility. Hitchhiking has been demonstrated to occur in two evolutionarily divergent species of filamentous fungi, Aspergillus nidulans and Ustilago maydis. In the K99 phase of this award, she will investigate a potential evolutionary advantage of peroxisome hitchhiking in A. nidulans and determine if mRNA hitchhiking convergently evolved in A. nidulans and U. maydis. In the R00 phase of this award, she will determine if hitchhiking occurs in a third filamentous fungus, Ashbya gossypiii, a fungus lacking canonical microtubule-based transport. Dr. Christensen’s goal is to develop an independent research program at the interface of cell and evolutionary biology. To accomplish this, she will attend conferences spanning fields and participate in UCSD- sponsored and MOSAIC UE5 initiatives focused on lab management and the transition to independence. She will receive guidance from her mentoring committee (faculty listed below) and her primary mentor, Sam Reck- Peterson. This development plan, combined with training in evolutionary biology (with Matt Daugherty, UCSD), mammalian cell vesicle trafficking assays (with Susan Ferro-Novick, UCSD), and A. gossypii (with Amy Gladfelter, UNC Chapel Hill) will prepare her to excel in an independent position.