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.

项目摘要 大脑功能的逐渐丧失和神经退化是不同门类衰老的共同特征。 了解中枢神经系统(CNS)在其整个生命过程中如何再生神经元是 对再生医学的兴趣。神经干细胞(NSC)与中枢神经系统发育和生物学的研究 一直是一个活跃的研究领域，然而，我们对调控 由于长期神经干细胞的稀有，在衰老过程中神经干细胞的动态有限，监测神经干细胞在 活体，以及小鼠和人类大脑令人难以置信的复杂性。在本提案中，我们试图了解基本的 神经元再生、变性和衰老的原理和进化保守元件 Botryllus schlosseri，一种具有简单中枢神经系统的原始脊索动物，表现为可分析的频繁(每周)中枢神经系统 在整个成年生活中，组织再生和退化可以在体内监测，这要归功于它几乎 透明的车身。这些生物可以通过配子进行有性繁殖，也可以通过茎进行无性繁殖。 细胞介导的发芽过程。随着新一代芽发育成成熟的个体(动物)，身体 古老的动物园经历了一波同步的细胞程序性死亡。在每周一次的再生和 退化周期在幼芽中形成新的大脑，与旧动物园的大脑的破坏相一致 (图1)。这个模型系统提供了一个独特的机会来研究细胞和分子机制， 年轻和老年群体的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 以确定积累在其中枢神经系统DNA中的突变，即在其整个生命周期中持续存在的干细胞。这个 Botryllus基因组编码数百个与哺乳动物同源的大脑相关基因。我们已经承诺 OLD的系统分子(转录)、细胞(FACS)形态和行为特征 和年轻的群体(图2)。Botryllus转录组分析显示与阿尔茨海默病相关的393个基因 疾病在年轻群体和老年群体之间有差异表达(图2C-D)。血液分析显示 老Botryllus菌落中吞噬细胞的频率增加(图2A-B)，类似于与年龄相关的 小鼠和人的HSC向髓系细胞转变。形态和功能分析发现，大脑 老菌落的数量更小，细胞数量更少，对刺激的反应也更弱(图2E-F)。 由于干细胞是唯一能自我更新并在整个菌落生命中保持的细胞，我们 假设随着时间的推移，在NSC中积累的基因突变是年龄相关的主要原因 神经退行性疾病。为了验证这一假设，我们计划表征分子和细胞的多样性。 分离其神经干细胞，鉴定在神经干细胞中积累的突变，并 祖细胞DNA，检测其对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.

• DOI: 10.3390/md19080454
• 发表时间: 2021-08-09
• 期刊: Marine drugs
• 影响因子: 5.4
• 作者: Goldstein O;Mandujano-Tinoco EA;Levy T;Talice S;Raveh T;Gershoni-Yahalom O;Voskoboynik A;Rosental B
• 通讯作者: Rosental B

Stemness Activity Underlying Whole Brain Regeneration in a Basal Chordate.

• DOI: 10.3390/cells11233727
• 发表时间: 2022-11-22
• 期刊: CELLS
• 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