Unraveling mechanisms of genome regulation to understand and improve human health

揭示基因组调控机制以了解和改善人类健康

• 批准号: 10488578
• 负责人: Justin Lee Cotney
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-09 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488578
• 关键词: Affect; Architecture; Brain; Cardiac development; Child; Code; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Diabetes Mellitus; Disease; Embryo; Embryonic Development; Evolution; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Code; Genome; Health; Heart; Human; Human body; Individual; Life; Limb structure; Link; Malignant Neoplasms; Modeling; Molecular; Natural Selections; Neurologic Dysfunctions; Organogenesis; Organoids; Pattern; Process; Proteins; Regulation; Regulatory Element; Research; Rest; Tissues; Variant; Work; cardiogenesis; craniofacial development; disease phenotype; disorder risk; genome annotation; improved; orofacial; orofacial cleft; postnatal development; prevent

Summary The human body is constructed during through tightly orchestrated patterns of gene expression during embryonic and postnatal development. Perturbations in gene regulation during development are thought to be a major substrate for natural selection and have likely contributed to the evolution of the human form. The molecular processes that contributed to sculpting human specific features of our limbs and brains, can have deleterious consequences when a critical gene or regulatory sequence is affected. Defective gene regulation during embryonic development can result in a variety of structural and functional defects such as congenital heart defects, orofacial clefting, or neurological dysfunction. In cases where a birth defect is not readily observed the individual may be instead be predisposed to various diseases later in life including diabetes or cancer. While our understanding of the genetic code for protein coding genes allows us to make predictions about disease risk our limited understanding of the information encoded in the rest of our genome prevents such predictions and causative assignments. Over the past several years functional annotations of the genome in tissue and developmental stage specific contexts have revealed over half a million potential regulatory elements. We and others have shown that variants linked to diseases and phenotypes of particular tissues are enriched in regulatory sequences that are active in those tissues or during their development. This has been particularly fruitful for defects related to craniofacial and heart development. The work proposed aims to build on these annotations to identify the genes that are controlled by these tissue-specific regulatory sequences and the consequences of variation in those sequences. Using culture and organoid models of early human cardiac development we aim to dissect the regulatory architecture that build the heart and malfunctions in congenital heart defects.

概括 人体是通过紧密协调的基因表达模式构建的 在胚胎和产后发育期间。基因调控过程中的扰动 发展被认为是自然选择的主要基础，并可能有助于 到人类形态的进化。有助于塑造人体的分子过程 我们的四肢和大脑的特定特征，当一个关键基因出现时，可能会产生有害的后果 或调节序列受到影响。胚胎发育过程中的基因调控缺陷可以 导致多种结构和功能缺陷，如先天性心脏病、口面部缺陷 裂或神经功能障碍。如果出生缺陷不易观察到， 相反，个体在以后的生活中可能容易患各种疾病，包括糖尿病或 癌症。虽然我们对蛋白质编码基因的遗传密码的理解使我们能够 关于疾病风险的预测我们对其余部分编码的信息了解有限 我们的基因组阻止了此类预测和因果分配。过去几年 组织和发育阶段特定环境中基因组的功能注释 揭示了超过 50 万个潜在的监管要素。我们和其他人已经证明 与疾病和特定组织表型相关的变异在调节方面丰富 在这些组织中或在其发育过程中活跃的序列。这已经特别 对于与颅面和心脏发育相关的缺陷非常有效。拟议的工作旨在建立 根据这些注释来识别受这些组织特异性调节控制的基因 序列以及这些序列中变异的后果。使用培养物和类器官 我们的目标是剖析早期人类心脏发育模型的监管架构 构建心脏和先天性心脏缺陷的功能障碍。