Origins of variation in mitochondrial metabolism

这些研究有助于定义细胞和遗传途径，这些途径是自然界中多样性的基础，使我们能够深入了解已知对我们自身代谢至关重要的途径的进化起源。这项工作主要是为了了解决定动物代谢生理学的关键基因多样性的进化起源，但结果与许多人类疾病有直接关系，这些疾病的病因与能量代谢有关，如糖尿病和缺血/再灌注。* 我的计划探讨了肌肉能量产生变化的起源和后果：肌肉代谢在需要时如何重塑，以及组织和动物之间的代谢机制如何因进化和发展而产生差异。通过比较和对比模型和实验方法，我们希望区分在动物中广泛保守的调控途径和那些负责特定组织和动物独特特征的调控途径。在下一个资助周期中，我们将利用不断增长的基因组信息数据库，开始梳理动物群体之间能量代谢差异的调节基础。最接近的问题集中在（i）肌肉代谢特性的差异如何在哺乳动物的谱系之间产生，以及（ii）在哺乳动物中至关重要的调节因子是否与原始脊椎动物共享。* 前两个目标集中在细胞色素c氧化酶的亚基上，该酶负责使用动物消耗的大部分氧气。其中一个亚基COX 4以两种形式存在于所有脊椎动物中。我们正在以前的研究基础上解释哺乳动物和不太复杂的脊椎动物之间的蛋白质差异。* 后两个目标集中在PGC 1，一个调节编码代谢蛋白的基因组表达的蛋白质家族。它的结构以赋予动物谱系不同功能的方式进化，因此它提供了一个模型来研究进化如何影响这种蛋白质的功能。* 该计划的安排是为了支持一个专注于4名研究生的实验室，为本科暑期学生和荣誉的论文学生提供额外的机会。这些实验将为希望更好地了解动物生理学、进化和细胞生物学之间相互作用的学生提供许多培训机会。所有这些高素质的人员将获得重要的技术培训，可用于解决学术和工业研究中的问题。

These studies help define the cellular and genetic pathways that are the underpinnings of diversity seen in nature, giving insight into the evolutionary origins of pathways known to be vital to our own metabolism. This work is done primarily to understand evolutionary origins of diversity in genes critical in determining the metabolic physiology of animals, but the results have direct relevance to the many human diseases with etiologies that are intertwined with energy metabolism, such as diabetes and ischemia/reperfusion. ***My program explores the origins and consequences of variation in muscle energy production: how muscle metabolism is remodelled when needed and how differences in metabolic machinery arise between tissues and animals as a consequence of evolution and development. By comparing and contrasting models and experimental approaches, we hope to distinguish between regulatory pathways that are broadly conserved among animals and those that are responsible for unique features of specific tissues and animals.***In the next grant cycle we take advantage of the growing database of genomic information to begin to tease apart the regulatory basis of differences in energy metabolism between groups of animals. The proximate questions focus on (i) how differences in muscle metabolic properties arise between lineages of mammals and (ii) whether the regulators that are critical in mammals are shared with primitive vertebrates. ***The first two objectives focus on a subunit of cytochrome c oxidase, the enzyme that is responsible for using most of the oxygen consumed by the animal. One subunit, COX4, is present in two forms in all vertebrates. We are building on previous studies to explain how the protein differs between mammals and less complex vertebrates. ***The second two objectives focus on PGC1, a family of proteins that regulate the expression of suites of genes encoding metabolic proteins. Its structure has evolved in ways that impart different functions in animal lineages, and thus it presents a model to study how evolution has influenced the function of this protein. ***The program is arranged in a way to support a lab focused on 4 graduate students, with additional opportunities for undergraduate summer students and Honour's thesis students. The experiments proposed will provide many training opportunities for students hoping to gain a greater understanding of the interactions between animal physiology, evolution and cell biology. All of these highly qualified personnel will gain important technical training that can be used to tackle questions in academic and industrial research.