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Cell Chirality Based In Vitro Models For Embryonic Development and Abnormalities

基于细胞手性的胚胎发育和异常体外模型

基本信息

批准号：
8757997
负责人：
Leo Q. Wan
金额：
$ 243万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Chirality, also known as handedness or left-right (LR) asymmetry, is a conserved feature in the development of multi-cellular organisms, and can be seen in the growth of climbing plants, the helices of snail shells, and the positioning of internal organs in the human body. For human, defects in laterality such as isomerism (loss of asymmetry), and heterotaxia (a loss of concordance among the individual organs) are observed in more than 1 in 8000 live births, and have significant clinical implications. In vertebrates, epithelial chiral morphogenesis is important in establishing the LR asymmetric body plan, from the early nodal flow at the ventral node to the later heart c-looping and gut asymmetric rotation. Traditionally, LR asymmetry is studied with animal embryos in vivo, which is often very challenging. The direct manipulation of human embryos is restricted because of the obvious ethical concerns. Recently, we have recapitulated epithelial chiral morphogenesis on micropatterned surfaces. Now we want to further develop in vitro systems for studying embryonic LR axis development. Our rationale is that novel cell chirality based high-throughput platforms and a better understanding of molecular mechanisms of epithelial cell chirality can greatly facilitate the LR asymmetry research in developmental biology. We propose to use a combination of embryonic stem cell culture, micro-fabrication, live cell imaging, molecular assay, traction force measurement, and high-throughput screening as tools to elucidate the underlying biophysical and biochemical mechanisms for epithelial chiral morphogenesis. Our objectives are to establish multiscale in vitro models for LR asymmetry in development and to identify important signaling pathways and cytoskeletal proteins that affect epithelial cell chirality. Specific Aim 1 (SA1): Establish and optimize multiscale in vitro models for studying LR asymmetry in development. We propose to improve our 2D multicellular model by matching substrate stiffness and ligand type with that of native embryonic tissue and to extend to models at single cell level and 3D tubular cell sheet. Specific Aim 2 (SA2): Determine effects and mechanisms of stem cell differentiation, growth factors, drugs that are important for LR asymmetry. We aim to establish a link between patterned epithelial cell chirality and developmental LR asymmetry. Specific Aim 3 (SA3): Determine cellular machinery mechanisms in patterned cell chirality. This will allow us to identify the ultimate cellular machinery for the emergence of chiral morphogenesis. Overall, if we are successful, these studies will establish novel, paradigm-shifting systems for measuring cell chirality in a high throughput fashion for studying LR asymmetry in development and disease, and screening genetic and biochemical factors that cause birth defects. In addition, this proposed research is transformative, and potentially open a new field of research: cell chirality, a fundamental cellular property defining the third axis of the cell.

描述（由申请人提供）：手性，也被称为手性或左右（LR）不对称，是多细胞生物发育中的一个保守特征，可以在攀缘植物的生长，蜗牛壳的螺旋和内部的定位中看到