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大致分为两类。第一个将衰老归因于分子和细胞机制的逐渐恶化，最终通过破坏生理稳态导致死亡；磨损模型。第二个观点表明，寿命是基因编程的，因此衰老可能源于内在过程，该过程强制有机体的生存能力有一个非随机的最终时间间隔。我们正在研究一种具有这两种特性的生物体：群体海鞘，Botryllus schlosseri。灰霉属属于被囊动物门，是脊椎动物的姐妹类群。除了这种密切的系统发育关系之外，葡萄孢属还具有许多生活史特征，这使其成为衰老研究的优秀模型。首先，灰霉病菌具有群体生活史，并通过无性繁殖过程生长，在此过程中，整个身体，包括所有体细胞和种系谱系，每周都会再生，形成一群基因相同的个体。一个菌落可以分裂成多个部分并继续生长，从而可以表征单个基因型一生中的遗传变化。此外，随着时间的推移，负责再生的干细胞可以被富集并表征其遗传和功能变化。其次，之前对遗传上不同的灰霉属谱系的寿命的研究表明，死亡率存在直接的、可遗传的基础，与繁殖努力和其他生活史特征无关。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全面的基因分析提供起点，从而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整个生命周期中对其进行分析。此外，我们还创建了进行正向和反向遗传筛选的基础设施。使用这些工具，我们将开始识别和表征这种新型脊索动物模型生物体衰老的遗传基础。 公共健康相关性：这些研究旨在剖析新模式生物——海鞘类 Botryllus schlosseri 的衰老过程。灰霉属是一种脊索动物，属于脊椎动物的祖先物种。海鞘的幼虫形式是脊索动物蝌蚪，但很快就会变态为无脊椎动物成虫，其具有复杂的身体结构，包括心脏、咽、胃肠道、神经系统、复杂的脉管系统和血液。灰霉属于海鞘的一个亚群，它们是群体性的，并且生长不是通过增大尺寸，而是通过每周再生整个身体，包括所有组织。这导致了一群基因相同的个体通过共同的血液供应相连。作为衰老模型，灰霉病最有力的方面之一是每个个体都可以分成几块，并且会继续生长。因此，我们可以独立研究个体的各个部分，随着群体年龄的增长，比较其再生能力。此外，灰霉属还具有其他一些有趣的衰老特征，包括实验室饲养和自然种群的两种不同的寿命（3个月和1年），以及单个个体的分离部分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独特的生活史特征和短暂的寿命。研究这种更简单的祖先生物体的衰老过程将提供其他物种所没有的机会和见解。