Aging and Regeneration in a basal chordate

描述(申请人提供)：旨在识别衰老机制的理论大致可分为两类。第一种将衰老归因于分子和细胞机制的逐渐恶化，最终通过破坏生理内稳态而导致死亡；磨损模型。第二种观点认为，寿命是由基因决定的，因此衰老可能源于内在的过程，这种过程为生物体的生存能力设定了一个非随机的、终极的时间间隔。我们正在研究一种表现出这两种特性的有机体：殖民地海鞘，施洛瑟氏博特鲁斯。Botryllus属于脊椎动物的姊妹群--脊椎动物门。除了这种密切的系统发育关系外，Botryllus还具有许多生活史特征，使其成为研究衰老的极佳模式。首先，Botryllus有殖民地生活史，并通过无性繁殖过程生长，在此过程中，整个身体，包括所有体细胞和生殖系谱系，每周都会再生，产生一群基因相同的个体。一个菌落可以被分成多个片段，并将继续增长，从而可以表征单一基因在一生中的遗传变化。此外，负责再生的干细胞可以随着时间的推移而丰富和表征遗传和功能的变化。其次，之前对不同的Botryllus血统的寿命的研究表明，存在直接的、可遗传的死亡基础，与生殖努力和其他生活史特征无关。我们最近开发了基因和基因组工具来识别和功能描述这一过程中涉及的基因，包括一个大型转录组数据库，它将为衰老过程中全面的基因图谱提供一个起点，允许识别参与再生和衰老的候选基因，然后可以分析不同衰老表型个体的寿命。此外，我们还建立了进行正向和反向基因筛查的基础设施。使用这些工具，我们将开始识别和表征这种新的脊索状模式生物衰老的遗传基础。 与公共卫生相关：这些研究旨在剖析一种新的模式生物--丛生海鞘动物--的衰老过程。Botryllus是脊索动物，属于脊椎动物的前体物种。海鞘类的幼虫是一只脊索状的蝌蚪，但很快就会蜕变成无脊椎动物的成体，它有一个复杂的身体平面，包括心脏、咽部、胃肠道、神经系统、复杂的血管和血液。Botryllus属于海鞘的一个子集，它们是殖民地的，并且每周都会通过再生整个身体，包括所有组织，而不是通过增加体型来生长。这导致了一群基因相同的个体通过共同的血液供应联系在一起。Botryllus作为衰老模型最强大的方面之一是，每个个体都可以被分成几个部分，并将继续生长。因此，我们可以独立地研究个体的各个部分，比较随着时间的推移，随着群体年龄的增长，再生能力的变化。此外，Botryllus还具有其他几个有趣的衰老特征，包括在实验室饲养的种群和自然种群(3mo.和1年)，以及单个个体的分离片段的随机和非随机衰老。在过去的15年里，我们一直在开发当代的遗传和基因组工具来剖析这些过程，使我们能够利用独特的生活史特征和短暂的寿命以及这种脊索模型。研究这种更简单的祖先有机体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.