Regulation of cell fate determination by hormone-active nutrients and phytochemicals

激素活性营养素和植物化学物质对细胞命运决定的调节

• 批准号: 122140-2013
• 负责人: Meckling, Kelly
• 金额: $ 2.62万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=545405
• 关键词: Regulation; cell; fate; determination; hormone

Vitamin D plays important roles in the development of a variety of tissues including bones and teeth and more recently has been implicated as a central player in the differentiation and maintenance of a number of other tissues. Vitamin D deficiency is associated with abnormalities in blood cell development, neurological disorders, bowel disease, impaired immune function and increased incidence of obesity related diseases and certain forms of cancer. There are multiple receptors for active metabolites of vitamin D (1,25 dihydroxyvitamin D3 or calcitriol) including the classic nuclear and membrane vitamin D receptor (VDRnuc, VDRmem), but more recently, we and others have identified a novel membrane receptor that is genetically distinct from VDR. This protein is described as a Membrane Activated Rapid Response to Steroid (MARRS) receptor for vitamin D. It is known by a number of other names and has important roles in assisting with protein folding, response and survival of cells when stressed, and in the proper assembly of protein complexes that are important for immune cell function, particularly of B-cells. Hormone-active nutrients like vitamin D, rarely act on their own, more frequently interacting with other hormones, cytokines and other non-nutritive components of foods. The currently research program examines the mechanisms by which vitamin D acts in models of blood cell development and in maturation and function of breast epithelial tissues. In particular we are examining the role of MARRS in development of these tissues and how absence of its function interferes with normal decisions cells typically make about whether to proliferate, mature, change function or die. We use human cell culture models and molecular techniques to over-express or knock out MARRS, and examine how the cells respond to normal stimuli including 1,25 D3, fatty acids, cytokines and phytochemicals such as those found in red wine. We are also generating mice that have MARRS missing in certain blood cell lineages and in specific breast epithelial cells to examine the impact on development of these tissues in mice and the role for vitamin D in their development, maintenance of cell function and susceptibility to disease.

维生素D在包括骨骼和牙齿在内的多种组织的发育中发挥着重要作用，最近被认为是许多其他组织的分化和维持的核心作用者。 维生素D缺乏与血细胞发育异常、神经系统疾病、肠道疾病、免疫功能受损以及肥胖相关疾病和某些形式的癌症的发病率增加有关。 维生素D的活性代谢物（1，25二羟基维生素D3或骨化三醇）有多种受体，包括经典的核和膜维生素D受体（VDRnuc，VDRnu），但最近，我们和其他人已经确定了一种新的膜受体，在遗传上与VDR不同。 这种蛋白质被描述为维生素D的膜激活类固醇快速反应（MARRS）受体。 它有许多其他名称，并且在帮助蛋白质折叠，应激时细胞的反应和存活以及蛋白质复合物的正确组装中具有重要作用，这些蛋白质复合物对免疫细胞功能，特别是B细胞的功能很重要。 激素活性营养素，如维生素D，很少单独起作用，更频繁地与其他激素，细胞因子和食物中的其他非营养成分相互作用。 目前的研究项目检查了维生素D在血细胞发育模型和乳腺上皮组织成熟和功能中的作用机制。 特别是，我们正在研究MARRS在这些组织发育中的作用，以及其功能的缺失如何干扰细胞通常做出的关于是否增殖，成熟，改变功能或死亡的正常决定。 我们使用人类细胞培养模型和分子技术来过度表达或敲除MARRS，并研究细胞如何对正常刺激做出反应，包括1，25 D3，脂肪酸，细胞因子和植物化学物质，如红酒中发现的那些。 我们还正在培育某些血细胞谱系和特定乳腺上皮细胞中缺失MARRS的小鼠，以研究对小鼠这些组织发育的影响以及维生素D在其发育、维持细胞功能和疾病易感性中的作用。