Human-specific gene changes in cranial sutures

颅缝中人类特异性基因变化

• 批准号: 8950538
• 负责人: Craig Barrett Lowe
• 金额: $ 13.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8950538
• 关键词: Affect; American; Animal Model; Antidepressive Agents; Area; Automobile Driving; Award; Biological Assay; Biological Models; Brain; Cells; Cephalic; Congenital abnormal Synostosis; Craniosynostosis; DNA; Data; Dental; Development; Developmental Biology; Disease; Disease susceptibility; Dura Mater; Engineering; Enhancers; Event; Exposure to; Funding; Genes; Genetic; Genomics; Goals; Growth; Head; Health; Histology; Human; Human Biology; Interdisciplinary Study; International; Jaw; Joint structure of suture of skull; Knockout Mice; Knowledge; Lead; Left; Link; Literature; Malocclusion; Mammalian Genetics; Mentors; Modeling; Molecular; Molecular Biology; Morphology; Mus; Mutation; Myopathy; Nucleic Acid Regulatory Sequences; Osteoblasts; Osteogenesis; Pattern; Phenotype; Physicians; Physiological; Pongidae; Predisposition; Pregnancy; Public Health; Regulatory Element; Reporting; Research; Research Activity; Research Infrastructure; Research Personnel; Research Project Grants; Risk; Rodent; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Signal Transduction; Skeletal Development; Structure; Surgical sutures; Surveys; System; Temporomandibular Joint Disorders; Testing; Time; Tissues; Training; Training Activity; Transgenic Organisms; Universities; Woman; Work; Writing; X-Ray Computed Tomography; base; bone; career; career development; computer science; craniofacial; craniofacial development; cranium; density; fetal; functional genomics; human disease; improved; innovation; insight; meetings; novel; novel strategies; postnatal; prenatal; professor; public health relevance; receptor; research and development; research study; serotonin receptor; skull abnormality; trait; translational medicine

 DESCRIPTION (provided by applicant): This award will both fund research to identify genomic mutations that have made humans uniquely susceptible to certain craniofacial disorders, as well as provide training and career development for Dr. Lowe to apply his quantitative background to research focusing on human health and disease. Mice have long been the favored system for mammalian genetics and development. Mice and humans share many fundamental features of mammalian development, making it possible to model many aspects of human health and disease using the mouse system. However, there are anatomical and physiological specializations in both species. For example, humans have a different dental pattern than rodents. Even compared to other great apes, humans have reduced jaws and greatly enlarged cranial capacity. The very traits that underlie human biology may also increase susceptibility to particular diseases, such as craniosynostosis and skull abnormalities, dental impaction, malocclusions, and temporomandibular joint and muscle disorders. It is now possible to begin understanding the molecular basis of human specific traits and disease susceptibilities, by combining large scale surveys of human specific DNA changes, with functional data on regulatory elements, flanking genes, and phenotypic effects in model systems. Multiple research studies have reported links between the serotonin system and skull development in humans, a link that has not been seen in mice. Dr. Lowe presents preliminary data showing that humans have a transposon insertion that upregulates expression of the serotonin receptor HTR1B in developing sutures, a molecular change likely to contribute to both delayed suture closure and sensitivity to serotonin signaling during skull development. During the award Dr. Lowe will: (1) identify the cells and tissues affected by the human specific enhancer, (2) recreate the human specific regulatory change and identify the phenotypes that result from similar expression of HTR1B in sutures of mice, (3) expand beyond this example to test whether similar lineage specific regulatory changes have reshaped other unique features of human craniofacial development. The results from this work are expected to have a positive impact on translational medicine by making physicians aware of the molecular mechanisms linking the serotonin system and skull development, and possibly suggesting new strategies for promoting suture patency when synostosis is detected early. This work will be conducted in the Developmental Biology Department at Stanford University and mentored by Professor David Kingsley, an expert in vertebrate genetics and skeletal development with an outstanding track record of preparing trainees for independent careers. Stanford University has extensive research infrastructure to support the proposed research. Dr. Lowe will receive formal training in histology, craniofacial development, and the use of xray computed tomography to quantify bone morphology, volume, and density. He will attend multiple Stanford, Bay Area, and international meetings in skeletal and craniofacial development, to provide broad exposure to problems and approaches in the field. Dr. Lowe will also be mentored by experts in molecular biology, genetics, and developmental biology to augment his background in computer science and immerse him in research projects related to human health and disease. Extensive practice in both speaking and writing will accompany the planned experimental work. The combination of research and training activities will prepare Dr. Lowe to become an independent investigator, managing his own interdisciplinary research lab. Dr. Lowe's unique background will bring innovative new approaches to the field, and should lead to important new insights into both the genomic and genetic basis of human craniofacial traits and disease susceptibilities that are unique to humans.

 描述（由申请人提供）：该奖项将资助识别基因组突变的研究，这些突变使人类特别容易患某些颅面疾病，并为 Lowe 博士提供培训和职业发展，以将他的定量背景应用于关注人类健康和疾病的研究。长期以来，小鼠一直是哺乳动物遗传和发育的首选系统。小鼠和人类具有哺乳动物发育的许多基本特征，使得利用小鼠系统模拟人类健康和疾病的许多方面成为可能。然而，这两个物种都有解剖学和生理学的特殊性。例如，人类的牙齿结构与啮齿类动物不同。即使与其他类人猿相比，人类的下巴也缩小了，颅骨容量也大大扩大了。人类生物学基础的特征也可能增加对特定疾病的易感性，例如颅缝早闭和颅骨异常、牙齿嵌塞、咬合不正以及颞下颌关节和肌肉疾病。通过将人类特定 DNA 变化的大规模调查与模型系统中调控元件、侧翼基因和表型效应的功能数据相结合，现在可以开始了解人类特定性状和疾病易感性的分子基础。多项研究报告了人类血清素系统与头骨发育之间的联系，但这种联系在小鼠身上尚未发现。 Lowe 博士提供的初步数据显示，人类有一个转座子插入，可在发育中的缝线中上调血清素受体 HTR1B 的表达，这种分子变化可能会导致颅骨发育过程中缝线闭合延迟和对血清素信号的敏感性。在获奖期间，Lowe 博士将：(1) 识别受人类特异性增强子影响的细​​胞和组织，(2) 重现人类特异性调节变化并识别小鼠缝线中 HTR1B 相似表达所产生的表型，(3) 扩展此示例，以测试类似的谱系特异性调节变化是否重塑了人类颅面发育的其他独特特征。这项工作的结果预计将对转化医学产生积极影响，让医生了解连接血清素系统和颅骨发育的分子机制，并可能提出在早期发现骨连接时促进缝线通畅的新策略。这项工作将在斯坦福大学发育生物学系进行，并由脊椎动物遗传学和骨骼发育专家 David Kingsley 教授指导，他在帮助学员为独立职业做好准备方面有着出色的记录。斯坦福大学拥有广泛的研究基础设施来支持拟议的研究。 Lowe 博士将接受组织学、颅面发育以及使用 X 射线计算机断层扫描来量化骨形态、体积和密度方面的正式培训。他将参加多个斯坦福大学、湾区以及骨骼和颅面发育方面的国际会议，以广泛了解该领域的问题和方法。 Lowe 博士还将得到分子生物学、遗传学和发育生物学专家的指导，以增强他在计算机科学方面的背景，并使他沉浸在与人类健康和疾病相关的研究项目中。计划中的实验工作将伴随着广泛的口语和写作练习。研究和培训活动的结合将使 Lowe 博士成为一名独立研究者，管理自己的跨学科研究实验室。 Lowe 博士的独特背景将为该领域带来创新的新方法，并且应该对人类颅面特征的基因组和遗传基础以及人类特有的疾病易感性产生重要的新见解。