A heterochronic model for birth defects in Down Syndrome

唐氏综合症出生缺陷的异时模型

• 批准号: 10658360
• 负责人: Ivan Paul Moskowitz
• 金额: $ 503.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658360
• 关键词: Affect; Basic Science; Binding; Birth; Brain; Cardiac; Cardiac Myocytes; Cell Count; Cell Differentiation process; Cell Line; Cells; Chromosome 21; Cilia; Complex; Congenital Abnormality; Defect; Development; Down Syndrome; Epigenetic Process; Equilibrium; Erinaceidae; Etiology; Failure; GLI gene; GLI3 gene; Gene Expression; Gene Expression Regulation; Genes; Genomics; Growth; Heart; Heart Abnormalities; Human; Human Chromosomes; In Vitro; Individual; Intellectual functioning disability; Kinetics; Laboratory Finding; Literature; Maintenance; Mediating; Microcephaly; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Neuronal Differentiation; Neurons; Organ; Organelles; Organogenesis; Pathology; Pathway interactions; Pattern; Population; Proliferating; Regulator Genes; Research Priority; Resolution; Signal Induction; Signal Transduction; Specific qualifier value; Structural defect; Testing; Time; Tissue-Specific Gene Expression; Translating; Work; atrioventricular septal defect; brain size; cell type; congenital heart disorder; gene regulatory network; genome-wide; hedgehog signal transduction; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; mortality; mouse model; multimodality; nerve stem cell; neural; novel; organ growth; premature; progenitor; response; stem cells; transcription factor

PROJECT SUMMARY The fundamental question for the field of Down Syndrome (DS) basic research is how an extra copy of human chromosome 21 (HSA21) translates into the organ-specific pathologies that are observed in the DS population. Structural pathologies in DS, such as brain size and heart malformation, are present at birth, and are generally associated with smaller organs or reduced growth. Therefore, they must be causally related to structural organogenesis defects, reflecting embryologic origins. A mechanistic understanding of DS-specific organogenesis defects is lacking in most cases, although a rich descriptive literature sets the stage for concerted mechanistic studies. Specifically, how Trisomy 21 (T21) causes heart or brain morphogenesis defects, causing CHD or intellectual disability, respectively, is poorly understood. The molecular networks identified by the proposed work, implicated in DS organ-specific cardiac and neuronal progenitors, will serve as a template for understanding the molecular ontogeny of heart and brain defects, as well as other organ defects, in DS. We have defined Hedgehog (Hh) signaling as an explicit development timer during mammalian development, required for maintaining organ-specific progenitor cells and dictating their differentiation in time and space, independent from developmental patterning or proliferation. The controlled balance between organ-specific progenitors and their differentiated counterparts is fundamental to complex organogenesis. The Moskowitz lab found that when Hh signaling is abrogated in cardiac progenitors, they underwent precocious differentiation, resulting in morphogenesis failure. Similarly, the Bhattacharyya lab has recently identified deficits in the Hh pathway in neuronal progenitors that controls their differentiation. We propose the transformative hypothesis that a unifying cause of birth defects in DS is failure of heterochronic timing control of organ-specific progenitor differentiation, resulting in precocious differentiation, a reduction of organ-specific progenitors, morphogenesis failure and birth defects in multiple organs.

项目摘要 唐氏综合症（DS）基础研究领域的根本问题是如何在一个额外的 人类21号染色体（HSA21）的拷贝转化为器官特异性病理， 在DS人群中观察到。DS中的结构病理学，如大脑大小和心脏 畸形，在出生时就存在，通常与较小的器官或减少 增长因此，它们必须与结构器官发生缺陷有因果关系， 胚胎起源对DS特异性器官发生缺陷的机制缺乏了解 在大多数情况下，虽然丰富的描述性文献为协调的机械论奠定了基础， 问题研究具体来说，21三体（T21）如何导致心脏或大脑形态发生缺陷， 冠心病或智力残疾，分别是知之甚少。分子网络识别出 通过拟议的工作，涉及DS器官特异性心脏和神经元祖细胞，将服务于 作为理解心脏和大脑缺陷的分子个体发生的模板，以及 其他器官缺陷，在DS。我们已经将Hedgehog（Hh）信号定义为一种明确的发展， 哺乳动物发育期间的定时器，维持器官特异性祖细胞所需 并决定它们在时间和空间上的差异，独立于发展模式 或扩散。器官特异性祖细胞及其分化细胞之间的受控平衡 是复杂器官形成的基础莫斯科维茨实验室发现， 信号传导在心脏祖细胞中被废除，它们经历早熟分化， 形态发生失败。同样，巴塔查里亚实验室最近发现了Hh 在神经元祖细胞中控制其分化的通路。我们提出了变革性的 假设DS中出生缺陷的统一原因是异时性时序控制失败， 器官特异性祖细胞分化，导致早熟分化， 器官特异性祖细胞、形态发生失败和多器官出生缺陷。