Genetic control of bone structure

骨架的骨骼由两种组织结构组成：皮质骨，形成长骨的外壳和中轴的高体积分数材料；松质骨是一种位于骨内部和骨端具有高孔隙度的开放晶格。迄今为止，骨组织工程还没有考虑到这两种结构的不同遗传调控。这项工作的目的是在松质骨和皮质骨分别调节的背景下，研究与年龄相关的遗传和分子机制。获得的信息对于理解和复制骨组织的形成、维持和退化至关重要。这些新数据将用于确定基因靶点和途径，以抑制或刺激基因表达和/或包膜特异性信号机制，以刺激和增强体内骨形成。主要的更广泛的影响目标集中在利用这项研究和PI的行政角色来提高女性在STEM教育和学术生涯中的参与度。该奖项由材料研究部的生物材料项目通过BioMaPs项目共同资助。骨骼的骨骼由两种组织结构组成：皮质骨，形成长骨的外壳和中轴的高体积分数材料；松质骨是一种位于骨内部和骨端具有高孔隙度的开放晶格。因此，如果试图复制这两种结构，它们独特的遗传控制是至关重要的。松质骨和皮质骨具有不同的发育途径，对生物物理刺激的适应也不同。例如，机械负荷是一种合成代谢生物物理刺激，可以增加骨量，逆转成人的骨质流失。机械生物学适应是不同的，并且是针对松质骨或皮质骨的。这两种结构受疾病的影响不同，通常松质比皮质的影响更大。不同的反应可能反映了两种组织之间不同的发育和机械感觉基因调控。然而，个体组织结构中的基因表达在生长或适应负荷期间尚未被检查。骨骼基因表达的途径已经通过基因敲除小鼠或对不区分两种组织类型的全骨进行基因分析进行了研究。所提出的工作的总体假设是，体内皮质骨和松质骨的基因表达不同，导致两种组织在生长过程中以及在机械负荷等扰动下的基因表达差异。研究小组证明：松质骨和皮质骨可以分别从生长小鼠的胫骨干骺端分离出来；有足够的mRNA可用并适合转录组学；松质骨和皮质骨在生长中的小鼠中表达不同的基因。通过rna测序和通路分析，本项目将1)分别定量测定生长和成年雌性小鼠胫骨松质骨和皮质骨中年龄相关基因的表达；2)在体内负荷后，利用生长和成年雌性小鼠胫骨中的差异基因表达，确定刺激合成代谢骨形成的潜在新靶点，这是PI实验室开发的一种不同影响松质和皮质骨组织的机械转导模型。获得的信息对于理解和复制骨组织的形成、维持和退化至关重要。这些新数据将用于确定基因靶点和途径，以抑制或刺激基因表达和/或包膜特异性信号机制，以刺激和增强体内骨形成。主要的更广泛的影响目标集中在利用这项研究和PI的行政角色来提高女性在STEM教育和学术生涯中的参与度。具体来说，PI将：1)通过基于拟议研究的研讨会，让中学女生参与STEM学习；2)让女学生参与她的研究实验室；3)增加学术界STEM部门的女性教员。

PI: van der Meulen, Marjolein C.Proposal #: 1605935The bones of the skeleton consist of two tissue structures: cortical bone, a high volume fraction material forming the outer shell and central shafts of long bones; and, cancellous bone, an open lattice with high porosity located in the interior and bone ends. To date bone tissue engineering has not considered the distinct genetic regulation of these two structures. The goal of this work is to examine age-related genetic and molecular mechanisms in the context of regulation of cancellous and cortical bone separately. Information obtained is critical to understanding and replicating bone tissue formation, maintenance and degeneration. The novel data will be used to identify genetic targets and pathways to inhibit or stimulate gene expression and/or envelope-specific signaling mechanisms to stimulate and enhance bone formation in vivo. The major broader impact objectives are focused on using this research and the PI's administrative role to enhance the participation of women in STEM education and academic careers. This award is co-funded by the Biomaterials program in the Division of Materials Research through the BioMaPs program.The bones of the skeleton consist of two tissue structures: cortical bone, a high volume fraction material forming the outer shell and central shafts of long bones; and, cancellous bone, an open lattice with high porosity located in the interior and bone ends. Thus their distinct genetic control is critical if one seeks to replicate these two structures. Cancellous and cortical bone have different developmental pathways and adapt differently to biophysical stimuli. For example, mechanical loading is an anabolic biophysical srtimulus that increases bone mass and can reverse bone loss in the adult. Mechanobiologic adaptation differs and is specific to cancellous or cortical bone. The two structures are differentially affected by disease, often with greater cancellous effect than cortical. The differing responses likely reflect different developmental and mechanosensory gene regulation between the two tissues. However, gene expression in the individual tissue structures has not been examined during growth or with adaptation to loading. The pathways underlying skeletal gene expression have been studied using knockout mice or with gene analyses of whole bones that do not differentiate between the two tissue types. The overall hypothesis of the proposed work is that gene expression differs in cortical and cancellous bone in vivo, leading to differential gene expression between the two tissues during growth and with perturbations such as mechanical loading. The research team has demonstrated: cancellous and cortical bone can be isolated individually from the tibial metaphysis of growing mice; sufficient mRNA is available and suitable for transciptomics; and, cancellous and cortical bone express different genes in growing mice. Using RNA-sequencing and pathway analysis, this project will 1) quantitate age-related gene expression in cancellous and cortical bone separately in the tibiae of growing and adult female mice; and, 2) identify potential new targets to stimulate anabolic bone formation using differential gene expression in the tibia of growing and adult female mice after in vivo loading, a mechanotransduction model developed by the PI's laboratory that differentially affects cancellous and cortical bone tissue. Information obtained is critical to understanding and replicating bone tissue formation, maintenance and degeneration. The novel data will be used to identify genetic targets and pathways to inhibit or stimulate gene expression and/or envelope-specific signaling mechanisms to stimulate and enhance bone formation in vivo. The major broader impact objectives are focused on using this research and the PI's administrative role to enhance the participation of women in STEM education and academic careers. Specifically the PI will: 1) engage middle school girls in STEM learning via workshops based on the proposed research; 2) involve female students in her research laboratory; and, 3) increase women faculty in STEM departments in academia.