Genetic analysis of bone strength

 描述（由申请人提供） 骨质疏松症是一种进行性骨质流失的疾病，导致骨骼脆弱和容易骨折。骨质疏松症主要是一种低骨强度的遗传性疾病;然而，强度不能在人体内测量。因此，关于力量变异的遗传基础，还有很多东西有待发现。在这里，我们提出了一个创新的遗传分析的一套全面的骨强度性状使用多样性远交（DO）小鼠。我们将绘制高分辨率的数量性状基因座（QTL）的广泛的骨性状，包括生物力学，形态，骨小梁和皮质微结构，骨髓肥胖，动态组织形态计量学和生物力学。我们还将使用一种创新的F1体内验证策略，该策略模拟了使用现有突变小鼠或使用CRISPR/Cas9产生的小鼠发现QTL的复杂遗传环境。我们将验证Rhobtb 3和Soat 1在调节骨强度和相关性状中的作用。在CC和DO小鼠的初步研究中，这些基因被鉴定为骨强度QTL的候选基因。在DO中鉴定的其他基因将使用现有的突变小鼠或通过使用CRISPR/Cas9开发突变体来选择和验证。我们的新的和创新的基因发现和验证的方法有可能显着增加我们的基本生物过程的理解，骨强度的变化，并导致发现新的治疗目标，预防和治疗骨脆性。

 DESCRIPTION (provided by applicant) Osteoporosis is a disease of progressive bone loss, leading to a weak and fracture prone skeleton. Osteoporosis is primarily a genetic disorder of low bone strength; however, strength cannot be measured in human in vivo. As a result, much remains to be discovered regarding the genetic basis of variation in strength. Here, we propose an innovative genetic analysis of a comprehensive suite of bone strength traits using Diversity Outbred (DO) mice. We will map high-resolution quantitative trait loci (QTL) for a wide array of bone traits including biomechanics, morphology, trabecular and cortical microarchitecture, marrow adiposity, dynamic histomorphometry and biomechanics. We will also use an innovative F1 in vivo validation strategy that mimics the complex genetic environment of QTL discovery using existing mutant mice or mice generated using CRISPR/Cas9. We will validate the role of Rhobtb3 and Soat1 in the regulation of bone strength and related traits. These genes were identified as candidates for bone strength QTL in a pilot study of CC and DO mice. Additional genes identified in the DO will be selected validated using existing mutant mice or through the development of mutants using CRISPR/Cas9. Our novel and innovative approach to gene discovery and validation has the potential to significantly increase our understanding of the basic biological processes that underlie variation in bone strength and lead to the discovery of novel therapeutic targets for the prevention and treatment of bone fragility.