Evolutionary Conserved Mechanisms of Neuronal Degeneration and Regeneration

神经元变性和再生的进化保守机制

• 批准号: 9979601
• 负责人: IRVING L. WEISSMAN
• 金额: $ 43.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979601
• 关键词: Activities of Daily Living; Adult; Age; Aging; Allogenic; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Antisense RNA; Apoptosis; Area; Behavioral; Biological Assay; Biological Models; Blood; Brain; Candidate Disease Gene; Cell Transplantation; Cells; Cellular Morphology; Chordata; Clonal Expansion; DNA; DNA Sequence Alteration; Development; Disease; Elements; Exhibits; Expression Profiling; Flow Cytometry; Fluorescence-Activated Cell Sorting; Frequencies; Gene Expression; Generations; Genes; Genetic Markers; Genome; Germ Cells; Hematopoietic Cell Production; Human; Image; Immune system; Individual; Invertebrates; Knowledge; Label; Life; Link; Lymphoid Cell; Mammals; Mediating; Methods; Modeling; Molecular; Monitor; Morphology; Mus; Mutation; Myeloid Cells; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Organism; Phagocytes; Population; Presenile Alzheimer Dementia; Process; RNA Sequences; Regenerative Medicine; Research; Role; Stimulus; Systems Biology; Testing; Time; Tissue-Specific Gene Expression; Tissues; Transplantation; age related neurodegeneration; asexual; brain cell; cell type; common symptom; design; differential expression; experience; experimental study; genetic manipulation; human old age (65+); in vivo; in vivo monitoring; interest; knock-down; life history; marine organism; nerve stem cell; nervous system development; presenilin-1; presenilin-2; progenitor; programs; real time monitoring; response; self renewing cell; single-cell RNA sequencing; stem cells; tissue degeneration; tissue regeneration; tool; transcriptome; transcriptomics

Project Summary Gradual loss of brain function and neurodegeneration are common features of aging throughout diverse phyla. Understanding how the central nervous system (CNS) regenerates neurons throughout its life is a major area of interest in regenerative medicine. The study of neural stem cells (NSC) and CNS development and biology has been an active field of research, however, our knowledge of the precise developmental programs that regulate NSC dynamics during aging is limited due to the rarity of long term NSCs, the difficulty of monitoring NSCs in- vivo, and the incredible complexity of mouse and human brains. In this proposal we seek to understand basic principles and evolutionary conserved elements of neuronal regeneration, degeneration and aging using Botryllus schlosseri, a primitive chordate with a simple CNS that exhibits assayable and frequent (weekly) CNS tissue regeneration and degeneration throughout adult life, that can be monitored in vivo thanks to its nearly transparent body. These organisms can reproduce either sexually through gametes, or asexually through a stem cell mediated budding process. As a new generation of buds develop into mature individuals (zooids) the bodies of the old zooids undergo a synchronized wave of programmed cell death. During this weekly regeneration and degeneration cycle new brains form within the young buds in concert with the destruction of the old zooids’ brain (Fig 1). This model system offers a unique opportunity to study the cellular and molecular mechanisms that direct weekly cycles of CNS generation and degeneration in young and old colonies (e.g. <3 months vs. >9 years) and to identify mutations that accumulate in the DNA of its CNS, stem cells that persist throughout its life. The Botryllus genome encodes hundreds of brain-associated genes with mammalian homologs. We have undertaken a systematic molecular (transcriptomic), cellular (FACS) morphological and behavioral characterization of old and young colonies (Fig 2). Botryllus transcriptome analyses revealed 393 genes that correlate with Alzheimer’s disease are differentially expressed between young and old colonies (Fig 2C-D). Blood analysis showed an increased frequency of phagocytic cells in old Botryllus colonies (Fig 2A-B), analogous to the age-associated shift in mouse and human HSC to favor myeloid cells. Morphological and functional analysis found that the brains of old colonies are smaller, contain a lower number of cells and have reduced response to stimuli (Fig 2E-F). Since stem cells are the only cells that self-renew and are maintained throughout the colony’s life, we hypothesize that genetic mutations that accumulate over time in NSC are the main cause of age associated neurodegenerative diseases. To test this hypothesis, we plan to characterize the molecular and cellular diversity of the Botryllus brain in young and old colonies, isolate its NSCs, identify mutations that accumulate in NSC and progenitor cells DNA, and test their effect on brain regeneration and function.

项目概要 大脑功能逐渐丧失和神经退行性变是不同门类衰老的共同特征。 了解中枢神经系统 (CNS) 在其一生中如何再生神经元是研究的一个主要领域 对再生医学（NSC）和中枢神经系统发育和生物学的研究产生了兴趣。 一直是一个活跃的研究领域，然而，我们对调节的精确发育程序的了解 由于长期 NSC 的稀有性、在衰老过程中监测 NSC 的困难，NSC 的动态受到限制。 体内，以及小鼠和人类大脑令人难以置信的复杂性在这个提案中，我们试图了解基本的知识。 利用神经再生、退化和衰老的原理和进化保守元素 Botryllus schlosseri，一种具有简单中枢神经系统的原始脊索动物，表现出可检测且频繁（每周）的中枢神经系统 整个成年期的组织再生和变性，由于其近乎可在体内进行监测 这些生物体可以通过配子进行有性繁殖，也可以通过茎进行无性繁殖。 当新一代芽发育成成熟个体（动物体）时，细胞介导的出芽过程。 旧的类动物在每周的再生过程中经历同步的程序性细胞死亡浪潮。 退化周期 新大脑在幼芽中形成，同时老动物大脑的破坏也随之而来 （图 1）该模型系统为研究指导的细胞和分子机制提供了独特的机会。 年轻和年老群体中中枢神经系统生成和退化的每周周期（例如<3个月与>9年）和 识别中枢神经系统 DNA 中积累的突变，即终生持续存在的干细胞。 我们已经研究了灰霉属基因组编码数百个与哺乳动物同源的大脑相关基因。 系统的分子（转录组）、细胞（FACS）形态和行为表征 和年轻菌落（图 2）。 疾病在年轻和年老的菌落之间有差异表达（图2C-D）。 老葡萄孢菌落中吞噬细胞的频率增加（图2A-B），类似于与年龄相关的 形态学和功能分析发现，小鼠和人类 HSC 向髓系细胞转变。 旧集落较小，细胞数量较少，对刺激的反应也较弱（图 2E-F）。 由于干细胞是唯一能够自我更新并在整个群体生命中得以维持的细胞，我们 认为 NSC 中随时间累积的基因突变是与年龄相关的主要原因 为了检验这一假设，我们计划表征分子和细胞多样性。 在年轻和年老的菌落中研究 Botryllus 大脑，分离其 NSC，识别 NSC 中积累的突变，并 祖细胞 DNA，并测试它们对大脑再生和功能的影响。

项目成果

Botryllus schlosseri as a Unique Colonial Chordate Model for the Study and Modulation of Innate Immune Activity.

Botryllus schlosseri 作为一种独特的殖民脊索动物模型，用于研究和调节先天免疫活动。

• 发表时间: 2021-08-09
• 影响因子: 5.4
• 作者: Goldstein, Oron;Mandujano;Levy, Tom;Talice, Shani;Raveh, Tal;Gershoni;Voskoboynik, Ayelet;Rosental, Benyamin
• 通讯作者: Rosental, Benyamin

Stemness Activity Underlying Whole Brain Regeneration in a Basal Chordate.

基底脊索全脑再生的干细胞活动。

• 发表时间: 2022-11-22
• 影响因子: 6
• 作者: Gordon, Tal;Zaquin, Tal;Kowarsky, Mark Alec;Voskoboynik, Yotam;Hendin, Noam;Wurtzel, Omri;Caicci, Federico;Manni, Lucia;Voskoboynik, Ayelet;Shenkar, Noa
• 通讯作者: Shenkar, Noa