Aging and Regeneration in a basal chordate

基底脊索动物的衰老和再生

• 批准号: 8307840
• 负责人: Anthony W De Tomaso
• 金额: $ 29.12万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307840
• 关键词: Adolescent; Adult; Affect; Age; Aging; Aging-Related Process; Animal Model; Asexual Reproduction; Backcrossings; Biological Metamorphosis; Blood; Candidate Disease Gene; Cells; Cessation of life; Characteristics; Chordata; Complex; Databases; Deterioration; Development; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Screening; Genomics; Genotype; Heart; Homeostasis; Individual; Invertebrates; Lead; Life; Link; Longevity; Maps; Modeling; Molecular; Molecular Profiling; Mutation; Natural regeneration; Nervous system structure; Organism; Parabiosis; Pharyngeal structure; Phenotype; Phylogenetic Analysis; Population; Positioning Attribute; Process; Property; RNA; RNA Interference; Research Design; Research Infrastructure; Sister; Staging; Stem cell transplant; Stem cells; Study models; Tadpoles; Techniques; Testing; Time; Tissues; Transplantation; Urochordata; Vascular blood supply; Vertebrates; ascidian; asexual; base; insight; interest; life history; mortality; novel; positional cloning; programs; public health relevance; regenerative; reproductive; research study; senescence; theories; time interval; tool; trait

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.

描述（由申请人提供）：旨在确定衰老机制的理论可以将其广泛分为两组。第一个属性衰老是分子和细胞机制中逐渐恶化的衰老，这最终通过破坏生理稳态而导致死亡。磨损模型。第二个表明寿命是遗传编程的，因此衰老可能是从内在过程中得出的，这些过程实施了生物体生存能力的非随机终端时间间隔。我们正在研究一种证明这两种特性的生物：殖民时期的海鞘，botryllus schlosseri。 botryllus属于脊椎动物的姐妹群，属于脊椎动物。除了这种紧密的系统发育关系外，Botryllus具有许多生活史特征，使其成为研究衰老的绝佳模型。首先，Botryllus具有殖民生活史，并通过无性繁殖的过程生长，在此过程中，包括所有体细胞和种系谱系在内，每周都会再生，从而导致遗传上相同的个体群落。一个菌落可以分为多个部分，并将继续增长，从而使遗传变化在单个基因型的生命周期内表征。另外，可以随着时间的推移而富集和表征负责再生的干细胞。其次，先前对遗传学上不同的botryllus谱系中的寿命的研究表明，存在直接，可遗传的基础死亡率，而存在于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，以识别和在功能上表征参与此过程的基因，包括一个大型转录组数据库，该数据库将为衰老过程中的全面基因分析提供一个起点，从而允许鉴定涉及重新衰老和衰老的候选基因，然后可以在不同的Aging Aging概况的个人中进行分析。此外，我们创建了基础架构以进行前进和反向遗传筛选。使用这些工具，我们将开始识别和表征这种新型脉络化模型生物体中衰老的遗传基础。 公共卫生相关性：这些研究旨在剖析新型模型生物体殖民地腹膜botryllus schlosseri中的衰老过程。 botryllus是一个核心，属于脊椎动物的前体的一组物种。海鞘的幼虫形式是脊柱t的，但很快将其变形为无脊椎动物成年人，其具有复杂的身体计划，其中包括心脏，咽，gi gi段，神经系统，神经系统，复杂的脉管系统和血液。 botryllus属于殖民地的一部分，不是通过增加大小，而是通过每周再生在内的整个身体（包括所有组织）再生。这导致由共同血液供应联系在一起的遗传学个体的菌落。 Botryllus作为衰老模型的最有力的方面之一是，每个人都可以分为几个部分，并将继续增长。因此，我们可以独立研究一个个体的部分，将随着时间的流逝比较再生能力，就像殖民地一样。此外，Botryllus还具有其他一些有趣的衰老特征，包括实验室和天然种群（3个月和1年）中的两个不同的寿命，以及单个分离碎片的随机和非随机衰老。在过去的15年中，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，从而使我们能够利用独特的生活历史特征，寿命短，以及这种脉络化模型。在这种更简单的祖先生物中研究衰老过程将提供其他物种中没有的机会和见解。