The molecular and cellular mechanisms of human brain expansion.

人脑扩张的分子和细胞机制。

• 批准号: RGPIN-2020-06345
• 负责人: Li, Yun
• 金额: $ 2.99万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761244
• 关键词: molecular; cellular; mechanisms; human; brain

The rapid evolutionary expansion of the human brain, in particular the cerebral neocortex, is the structural foundation of our unique intellectual abilities. The extraordinary size and extensively folded shape of the human brain makes it distinct from the brains of other mammals, including our primate relatives. During fetal development, neural stem cells undergo highly controlled proliferation and differentiation processes to generate the neurons and glia that make up the postnatal brain. It has been hypothesized that changes in the behaviours of human neural stem cells may be directly responsible for the expansion and folding of the human brain. In particular, distinct subtypes of neural stem cells that are abundant in the primate brains but absent in the mouse brains may contribute to brain expansion in the primate lineage. However, these hypotheses are largely untested, due to the inaccessible nature of the fetal human and non-human primate brains. As a result, our knowledge of the molecular and cellular mechanism that underlies human brain expansion remains extremely limited. My previous research has shown that crucial steps of human brain formation can be mimicked in the dish, thereby circumventing the need of human fetal tissues. We achieved this by deriving pluripotent stem cells from human skin cells, and then differentiating these stem cells into neurons and brain organoids. In the proposed research, my team will apply this strategy to create an innovative multi-species stem cell platform to study brain development in human, non-human primates, and mouse. We anticipate that the direct comparison of neural cells and brain organoids from human (a primate with large, folded brain), macaque (a primate with intermediate, folded brain), marmoset (a primate with small, smooth brain), and mouse (a rodent with very small, smooth brain) will provide unprecedented insights into the molecular, cellular, and anatomical mechanisms that regulate brain expansion and folding. The strategies, techniques, and infrastructure used in my research program will provide HQPs with cutting-edge training in stem cell engineering, gene editing, genomics analysis and high throughput assays. Understanding how the human brain forms and what makes it unique is the cornerstone for understanding who we are. Discoveries made in this work will advance the fields of stem cell biology and neurobiology, as well as have broad impact on studies of human biology.

人类大脑的快速进化扩张，特别是大脑新皮层，是我们独特智力的结构基础。人类大脑的非凡尺寸和广泛折叠的形状使其与其他哺乳动物的大脑不同，包括我们的灵长类亲戚。在胎儿发育期间，神经干细胞经历高度受控的增殖和分化过程，以产生构成出生后大脑的神经元和神经胶质。据推测，人类神经干细胞行为的变化可能直接导致人类大脑的扩张和折叠。特别是，灵长类动物大脑中丰富但小鼠大脑中不存在的不同亚型的神经干细胞可能有助于灵长类动物谱系的大脑扩张。然而，由于人类胎儿和非人类灵长类动物大脑的不可接近性，这些假设在很大程度上尚未得到验证。因此，我们对人类大脑扩张的分子和细胞机制的了解仍然非常有限。 我之前的研究表明，人类大脑形成的关键步骤可以在培养皿中模拟，从而避免了对人类胎儿组织的需求。我们通过从人类皮肤细胞中获得多能干细胞，然后将这些干细胞分化为神经元和脑类器官来实现这一目标。在拟议的研究中，我的团队将应用这一策略创建一个创新的多物种干细胞平台，以研究人类，非人类灵长类动物和小鼠的大脑发育。我们预计，来自人类（一种具有大的折叠大脑的灵长类动物），猕猴（一种具有中间折叠大脑的灵长类动物），绒猴（一种具有小而光滑大脑的灵长类动物）和小鼠（一种具有非常小而光滑大脑的啮齿类动物）的神经细胞和脑类器官的直接比较将为调节大脑扩展和折叠的分子，细胞和解剖机制提供前所未有的见解。在我的研究计划中使用的策略，技术和基础设施将为HQP提供干细胞工程，基因编辑，基因组学分析和高通量检测方面的尖端培训。了解人类大脑是如何形成的，是什么使它独一无二，是理解我们是谁的基石。这项工作的发现将推动干细胞生物学和神经生物学领域的发展，并对人类生物学研究产生广泛影响。