Nutritional factors and interactions in musculoskeletal biology

我的基础研究计划的长期目标是形成新的知识和培训受营养影响的骨生物学方面的熟练专业人员。短期目标将在未来5年内在啮齿动物模型中完成，以确定omega-3脂肪增加骨密度的全身和局部机制。与钙和维生素D在骨骼生物学中发挥重要作用的长期知识相比，这项工作是非常新的。维生素D被用来制造一种名为骨化三醇的激素，它通过与骨细胞核心的受体结合来控制骨骼代谢，骨细胞核心被称为基因所在的细胞核。有趣的是，一种被称为二十二碳六酸(或简称DHA)的欧米茄-3脂肪通常从脂肪丰富的鱼类中获得，它也与更强壮的骨骼有关。这甚至是在考虑了饮食中钙和维生素D的重要作用之后。我们现在希望证明DHA也与骨细胞核中的受体结合，这就是它调节与骨生物学相关的基因的方式。从我们之前的研究来看，DHA通过减少骨丢失发挥作用，在我们最近的工作中，它似乎与更多的肌肉和质量相关地促进了骨的形成。科学家需要了解身体如何利用这种欧米茄脂肪来增强骨骼和肌肉，因为这将导致进一步的发现。这个问题是NSERC发现基金的基本原理。为了探索DHA改变骨骼和肌肉的方式，将少量的DHA喂给各种动物3个月。在研究开始和结束时，使用非侵入性X射线技术来创建骨骼和骨骼内部(如腿骨)的图像。这些x射线还可以量化骨骼中的矿物质含量以及肌肉质量。其他技术也被用来使用显微镜和测量哪些基因被激活来显示骨骼中哪些蛋白质发生了变化。从腿部静脉采集微小的血液样本，测量DHA以及荷尔蒙和蛋白质，这些激素和蛋白质被输送到它们活动的地方的骨骼。将检查从肌肉释放到骨骼表面的因子。在实验室中培养的骨细胞将被用来证明DHA是通过一个“锁和钥匙”系统工作的。结合DHA在骨骼中的核受体蛋白将通过使用与受体结合并阻止DHA作用的药物来阻断。这项研究是新颖的，因为还没有研究人员发现DHA如何在骨骼中发挥作用，以及如何应对肌肉质量增加。知道这个问题的答案很重要，因为多年来，钙和维生素D一直是营养和骨生物学的支柱。学习新的营养素将带来对营养学和骨骼细胞如何工作的新理解。作为一项研究培训计划，许多高素质的年轻专业人员将在五年内使用高度尖端的技术进行培训。这样的培训将使他们能够在这种知识、技能和类似技术备受追捧的行业、学术界或政府中成功地从事研究工作。

The long-term objective of my basic research program is to formulate new knowledge and training of skilled professionals in the biology of bone as influenced by nutrition. The short-term objectives will be completed over the next 5 years in rodent models to identify whole body and local mechanisms by which omega-3 fats increase bone density. This work is very new compared to the longstanding knowledge that calcium and vitamin D play important roles in skeletal biology. Vitamin D is used to make a hormone called calcitriol which controls bone metabolism by binding to receptors in the core of bone cells, called the nucleus where genes are located. Interestingly, an omega-3 fat called docosahexanoic acid (or DHA for short) commonly obtained from fatty fish is also linked to stronger bones. This is even after accounting for the important roles of dietary calcium and vitamin D. We now wish to prove that DHA also binds to receptors in the nucleus of bone cells and that this is how it regulates genes related to bone biology. From our previous studies, DHA works by reducing bone loss and in our recent work it seems to increase bone formation in association with more muscle  mass. Scientists need to understand how the body uses this omega fat to enhance bone and muscle as it will lead to further discovery. This question is the rationale for this NSERC Discovery grant. To explore the ways that DHA alters bone and muscle, small amounts of DHA are fed to various animal species for 3 months. At the beginning and end of the study, non-invasive x-ray techniques are used to create images of the skeleton and the inside of bones such as the leg bone. These x-rays also quantify how much mineral is packed into bone as well as the amount of muscle mass. Other techniques are used to show which proteins are altered in bone using microscopes and by measuring which genes are turned on. Tiny blood samples are taken from a leg vein and measured for DHA plus hormones and proteins that are delivered to bone where they act. Factors released from muscle to the surface of bone will be examined. Bone cells grown in the laboratory will be used to prove that DHA works through a "lock and key" system. Nuclear receptor proteins that bind DHA in bone will be blocked by using drugs that bind to the receptor and prevent the action of DHA. This research is novel since no researcher has yet discovered how DHA works in bone and in response to enhanced muscle mass. Knowing answers to this question is important since for years calcium and vitamin D has been the mainstay of nutrition and bone biology. Learning about novel nutrients will bring new understanding in nutrition and how bone cells work. As a research training program, many highly qualified young professionals will be trained over five years using highly sophisticated technology. Such training will enable successful research careers in industry, academia or government where this knowledge, skill and similar technology are highly sought after.