Aging and Regeneration in a basal chordate

描述（由申请人提供）：旨在确定衰老机制的理论可以大致分为两组。第一种将衰老归因于分子和细胞机制的逐渐退化，最终通过生理稳态的破坏导致死亡;磨损模型。第二个建议，寿命是遗传编程，因此，老化可能是来自内在的过程，强制执行一个非随机的，终端的时间间隔的生存能力的有机体。我们正在研究一种同时具有这两种特性的生物：殖民海鞘，Botryllus schlosseri。Botryllus属于被膜动物门，是脊椎动物的姐妹类群。除了这种密切的系统发育关系外，葡萄球菌还具有许多生活史特征，这使其成为研究衰老的极好模型。首先，葡萄球菌有一个殖民生活史，并通过无性繁殖过程生长，在此过程中，整个身体，包括所有的体细胞和生殖系，每周再生，导致一个遗传相同的个体群体。一个菌落可以被分成多个部分，并将继续生长，允许在单个基因型的生命周期内表征遗传变化。此外，可以富集负责再生的干细胞，并表征其随时间的遗传和功能变化。第二，以前的研究寿命在遗传上不同的Botryllus谱系表明，一个直接的，遗传的基础上存在的死亡率是无关的生殖努力和其他生活史特征。我们最近开发了遗传和基因组工具来识别和功能表征参与这一过程的基因，包括一个大型转录组数据库，该数据库将为衰老过程中的综合基因分析提供起点，允许识别参与再生和衰老的候选基因，然后可以在不同衰老表型的个体的生命周期内进行分析。此外，我们还建立了进行正向和反向基因筛查的基础设施。利用这些工具，我们将开始确定和描述这种新的脊索动物模型生物体衰老的遗传基础。 公共卫生相关性：这些研究旨在剖析一种新的模式生物--殖民地海鞘Botryllus schlosseri的衰老过程。Botryllus是脊索动物，属于脊椎动物的前体物种。海鞘的幼虫形式是脊索动物蝌蚪，但很快就变成了无脊椎动物的成年人，它有一个复杂的身体计划，包括心脏，咽，胃肠道，神经系统，复杂的脉管系统和血液。Botryllus属于海鞘的一个子集，它们是殖民地，并不是通过增加大小来生长，而是通过每周再生整个身体，包括所有组织。这导致了一个由共同血液供应连接的基因相同的个体组成的群体。Botryllus作为衰老模型最强大的方面之一是，每个个体都可以分成几块，并将继续生长。因此，我们可以独立地研究个体的各个部分，随着时间的推移，随着殖民地的老化，比较它们的再生能力。此外，Botryllus还具有其他几个有趣的衰老特征，包括实验室饲养和自然种群中两种不同的寿命（3个月）。和1年），以及随机和非随机衰老的分离件的一个单一的个人。在过去的15年里，我们一直在开发当代遗传和基因组工具来剖析这些过程，使我们能够利用这种脊索动物模型的独特生活史特征和短寿命。研究这种更简单的祖先生物的衰老过程将提供其他物种所没有的机会和见解。

DESCRIPTION (provided by applicant): Theories which aim to identify the mechanisms of aging can be broadly classified into two groups. The first attributes aging to progressive deterioration in the molecular and cellular machinery which eventually lead to death through the disruption of physiological homeostasis; the wear-and-tear model. The second suggests that life span is genetically programmed, and therefore aging may be derived from intrinsic processes which enforce a non-random, terminal time interval for the survivability of the organism. We are studying an organism that demonstrates both properties: the colonial ascidian, Botryllus schlosseri. Botryllus belongs to the phylum Tunicata, the sister group to the vertebrates. Besides this close phylogenetic relationship, Botryllus has a number of life history traits which make it an excellent model for studies on aging. First, Botryllus has a colonial life history, and grows by a process of asexual reproduction during which entire bodies, including all somatic and germline lineages, regenerate every week, resulting in a colony of genetically identical individuals. A colony can be split into multiple pieces and will continue to grow, allowing the characterization of genetic changes over the lifetime of a single genotype. In addition, the stem cells responsible for regeneration can be enriched and characterized for both genetic and functional changes over time. Second, previous studies of lifespan in genetically distinct Botryllus lineages suggest that a direct, heritable basis underlying mortality exists that is unlinked to reproductive effort and other life history traits. We have recently developed the genetic and genomic tools to identify and functionally characterize genes involved in this process, including a large transcriptome database which will provide a starting point for comprehensive gene profiling during aging, allowing the identification of candidate genes involved in regeneration and aging, which can then be analyzed over the lifespan of individuals of different aging phenotypes. In addition, we have created the infrastructure to carry out both forward and reverse genetic screens. Using these tools we will begin to identify and characterize the genetic basis of aging in this novel chordate model organism. PUBLIC HEALTH RELEVANCE: These studies are designed to dissect the aging process in a new model organism, the colonial ascidian Botryllus schlosseri. Botryllus is a Chordate, and belongs to a group of species that are the precursors of the vertebrates. The larval form of ascidians is a chordate tadpole, but that soon metamorphoses into an invertebrate adult, which has a complex body plan that includes a heart, pharynx, GI tract, nervous system, complex vasculature and blood. Botryllus belongs to a subset of ascidians that are colonial, and grow, not by increasing in size, but by regenerating entire bodies, including all tissues, each and every week. This results in a colony of genetically identical individuals linked by a common blood supply. One of the most powerful aspects of Botryllus as a model for aging is that each individual can be separated into several pieces and will continue to grow. Thus we can study pieces of an individual independently, comparing regenerative abilities over time, as the colony ages. In addition, Botryllus also has several other interesting aging characteristics, including two distinct lifespans in both lab-reared and natural populations (3 mos. and 1 yr), as well as both random and non-random senescence of separated pieces of a single individual. Over the last 15 years we have been developing contemporary genetic and genomic tools to dissect these processes, allowing us to utilize the unique life history traits and short lifespan and of this chordate model. Studying the aging process in this simpler, ancestral organism will provide opportunities and insights not available in other species.