Dissertation Improvement: Elucidation of Hominid Vertebropelvic Evolution via Observational and Experimental Analyses of Murine Embryogenetics and Avian Developmental Biology

论文改进：通过小鼠胚胎遗传学和鸟类发育生物学的观察和实验分析阐明原始人类椎骨盆腔进化

• 批准号: 0352170
• 负责人: Owen Lovejoy
• 金额: --
• 依托单位: Kent State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0352170&HistoricalAwards=false
• 关键词: Dissertation; Improvement; Elucidation; Hominid; Vertebropelvic

The embryology and development of the human vertebral column and pelvis are important in a broad range of contexts, including the etiology and causation of human birth defects, as well as the normal growth and maturation of the trunk, pelvis, and lower limb. Other important areas include the identification of factors that affect overall pelvic form in ways that impact obstetric difficulty and success. The anatomy of this region is also central to our understanding of the process of human and primate evolution, especially the appearance and progressive adaptation of the lower limb to upright walking. A complete understanding the vertebral and pelvic embryology ultimately requires knowledge of their developmental genetics. In this research, three embryological models of the developmental progress of the sacrum, including a number of its important special features, such as segmental fusion, will be examined. Each makes different predictions with respect to the tempo and mode of sacroiliac change. Resolving which model is most accurate (and therefore most likely to be correct) requires a more thorough knowledge of this region's developmental biology. Given the rarity of specimens and the prolonged developmental period of primates (and other practical prohibitions as well), the researchers will perform skeletal analyses of mouse gene "knockouts" and examine chick embryological manipulations. These are effective alternatives to direct examination of the embryological processes in primates and humans. Recent gene knockouts (i.e., the targeted deactivation of a specific gene's normal activity) include a number that have a profound effect on normal spine and pelvis development. These include Pitx1, Emx2, Fgf10, and Fgf4-Fgf8. Examination of the role of each can potentially illuminate central aspects of the developmental (and thereby naturally selected) "units" of the pelvic girdle and lower limb, as well as clarify the developmental relationships between the pelvic bones and sacrum. High resolution microCT scans of mice in which one of these genes has been "deactivated" will be examined. Quantitative measures will be made of the three dimensional structure of the pelvis and spine in each mutant using NIH software. Identical procedures will be applied to normal mice of the same strain. In addition, fate maps of embryological tissues of the sacrum and pelvis will be examined in chicks in which transplantations of quail donor cells have been introduced. This technique has not been used previously to answer questions about vertebropelvic development in humans. Combining these data (mouse gene knockouts and avian embryological manipulation) will enhance our understanding of a crucially important and relatively new avenue of human evolutionary research, i.e., determining the biological effects of key genes (and their downstream targets) in shaping the human frame. As understanding of the human genome unfolds, anthropologists must keep pace by improving our understanding of those genes which are central to human anatomy and evolution. In addition, broader issues of evolution in limbed animals such as limb loss in snakes and whales, as well as the evolution of variations of spinal segmentation promise to be further illuminated by this research. A substantial proportion of the work to be conducted involves support and maintenance of the microCT laboratory at the Northeast Ohio Universities College of Medicine (NEOUCOM). This facility is vital to a variety of current clinical projects involving bone and cartilage growth and development. The work will also enhance world-wide scientific cooperation as a number of the mutant specimens that will be examined have been developed in Europe, Japan, Canada, as well as the United States. Agreements for the exchange of data derived from these specimens have already been arranged. NSF support will allow at least one anthropology graduate student to complete the Ph.D. Finally, enhancement of our understanding of these fundamental developmental processes is very likely to prove vital in furthering our capacity to diagnose and treat serious embryological defects.

人类脊柱和骨盆的胚胎学和发育在广泛的背景下都是重要的，包括人类出生缺陷的病因和原因，以及躯干、骨盆和下肢的正常生长和成熟。其他重要的领域包括确定以影响产科困难和成功的方式影响整体骨盆形状的因素。这一区域的解剖学也是我们理解人类和灵长类动物进化过程的核心，特别是下肢对直立行走的出现和逐渐适应。完全了解脊椎和骨盆胚胎学最终需要了解它们的发育遗传学。在这项研究中，将考察三种关于骶骨发育过程的胚胎学模型，包括它的一些重要的特殊特征，如节段性融合。每个人都对骶骨变化的节奏和模式做出了不同的预测。要确定哪种模型最准确(因此最有可能是正确的)，需要对该地区的发育生物学有更全面的了解。考虑到标本的稀缺性和灵长类动物较长的发育期(以及其他实际的禁止措施)，研究人员将对小鼠的“基因敲除”进行骨骼分析，并检查鸡的胚胎操作。这是直接检查灵长类动物和人类胚胎过程的有效替代方法。最近的基因敲除(即特定基因正常活动的靶向失活)包括一些对正常脊柱和骨盆发育有深远影响的基因。其中包括Pitx1、Emx2、Fgf10和Fgf4-Fgf8。对每一个角色的研究可以潜在地阐明骨盆腰带和下肢的发育(从而自然选择的)“单位”的中心方面，以及阐明骨盆骨骼和骶骨之间的发育关系。我们将对这些基因中有一种被“失活”的小鼠进行高分辨率的显微CT扫描。将使用NIH软件对每个突变体的骨盆和脊柱的三维结构进行定量测量。同样的程序将应用于相同品系的正常小鼠。此外，还将检查引入了鹌鹑供体细胞移植的雏鸡的骶骨和骨盆胚胎组织的命运图。这项技术以前从未被用来回答有关人类椎骨骨盆发育的问题。结合这些数据(小鼠基因敲除和鸟类胚胎操作)将增强我们对人类进化研究中一个至关重要且相对较新的途径的理解，即确定关键基因(及其下游靶标)在塑造人类框架方面的生物学效应。随着对人类基因组的了解的展开，人类学家必须通过提高我们对那些对人类解剖学和进化至关重要的基因的理解来跟上步伐。此外，四肢动物进化的更广泛问题，如蛇和鲸鱼的肢体丧失，以及脊柱分段变异的进化，有望通过这项研究进一步阐明。将开展的大部分工作涉及支持和维护东北俄亥俄大学医学院(NEOUCOM)的微型CT实验室。这一设施对目前涉及骨和软骨生长和发育的各种临床项目至关重要。这项工作还将加强世界范围内的科学合作，因为欧洲、日本、加拿大和美国已经开发了一些将被检测的突变标本。交换从这些标本获得的数据的协议已经安排好了。NSF的支持将允许至少一名人类学研究生完成博士学位。最后，加强我们对这些基本发育过程的理解，很可能对进一步提高我们诊断和治疗严重胚胎缺陷的能力至关重要。