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 脑功能和神经退行性的逐渐丧失是整个潜水员门的衰老的常见特征。 了解中枢神经系统（CNS）如何使神经元在其一生中再生是一个主要领域 对再生医学的兴趣。神经干细胞（NSC）和CNS发育和生物学的研究具有 但是，是一个积极的研究领域，我们对调节的精确发展计划的了解 由于长期NSC的稀有性，衰老过程中的NSC动力学受到限制，因此难以监测NSC In- 体内，以及小鼠和人类大脑的令人难以置信的复杂性。在此提案中，我们试图了解基本 原理和进化构成了使用神经元再生，退化和老化的元素 botryllus schlosseri，一种具有简单CNS的原始核心，表现出可分析和经常（每周）CNS 整个成人生活中的组织再生和变性，可以在体内对其进行监测，几乎谢谢它 透明的身体。这些生物可以通过游戏性或无性地通过茎来繁殖 细胞介导的出芽过程。随着新一代的芽发展成成熟个体（Zooid）的身体 旧的动物体经历了同步的编程细胞死亡波。在这个每周再生期间 堕落循环在年轻芽中形成新的大脑，与旧动物体大脑的破坏一起 （图1）。该模型系统提供了一个独特的机会来研究直接的细胞和分子机制 中枢神经系统的每周周期和年轻殖民地的变性（例如<3个月对> 9年）和 为了鉴定积累在其中枢神经系统DNA中的突变，其一生中持续存在的干细胞。 botryllus基因组用哺乳动物同源物编码数百个与脑相关的基因。我们已经承担了 旧的系统分子（转录组），细胞（FACS）形态和行为表征 和年轻的殖民地（图2）。 Botryllus转录组分析揭示了393个基因与阿尔茨海默氏症相关 疾病在年轻人和老年菌落之间的表达不同（图2C-D）。血液分析表明 与年龄相关的旧botryllus菌落中吞噬细胞的频率增加（图2A-B） 小鼠和人类HSC转移以有利于髓样细胞。形态学和功能分析发现大脑 旧菌落的较小，包含较少的细胞，并且对刺激的反应减少了（图2E-F）。 由于干细胞是唯一自我更新并在整个殖民地生活中保持的细胞，我们 假设随着时间的推移在NSC中积累的遗传突变是与年龄相关的主要原因 神经退行性疾病。为了检验这一假设，我们计划表征分子和细胞多样性 在年轻和老年菌落中的botryllus脑，分离其NSC，鉴定出在NSC和 祖细胞DNA，并测试其对脑再生和功能的影响。

项目成果

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

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