Epigenetic regulation of skeletal patterning and morphogenesis during development

发育过程中骨骼模式和形态发生的表观遗传调控

• 批准号: 9242599
• 负责人: Satya K. Kota
• 金额: $ 11.27万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-14 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242599
• 关键词: Adult; Affect; Alpha Cell; Anterior; Area; Basic Science; Bilateral; Binding; Binding Sites; Bioinformatics; Biology; Cells; Cephalic; ChIP-seq; Chromatin; Congenital Abnormality; Congenital Limb Deformities; Cytosine; DNA; DNA Methylation; DNA Modification Process; Data; Defect; Deformity; Dental Schools; Development; Developmental Gene; Digit structure; Disease; Distal; Down-Regulation; Educational workshop; Embryo; Embryonic Development; Enzymes; Epigenetic Process; Etiology; Event; Family; Family member; Forelimb; Foundations; Gene Deletion; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Growth; Histone Deacetylation; Histones; Homeostasis; Human; Immune System Diseases; In Vitro; Individual; Institutes; Knowledge; Lead; Limb Bud; Limb Development; Limb structure; Maintenance; Maps; Mediating; Mediator of activation protein; Medicine; Mentored Research Scientist Development Award; Mentors; Mesenchymal; Mesenchyme; Methyl-CpG-Binding Protein 2; Molecular; Molecular Analysis; Morphogenesis; Morphology; Motor Skills; Mus; Mutation; Neurodevelopmental Disorder; Newborn Infant; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Pattern; Phase; Phenotype; Positioning Attribute; Protein Binding Domain; Reader; Recruitment Activity; Regulation; Research; Research Methodology; Research Personnel; Research Training; Rett Syndrome; Role; SHFM1 gene; Signal Transduction; Skeletal Development; Stem cells; Stromal Cells; Targeted Research; Therapeutic; Tissues; Training; Universities; base; bone; cell type; chromatin remodeling; craniofacial; craniofacial development; developmental disease; epigenetic regulation; epigenomics; experience; gain of function; gene repression; genome-wide; genome-wide analysis; histone methylation; implantation; insight; interest; malformation; member; methyl group; mouse model; multidisciplinary; osteoprogenitor cell; pluripotency; progenitor; public health relevance; regenerative; response; skeletal; skeletal disorder; skeletal tissue; small hairpin RNA; spatiotemporal; stem cell biology; transcriptome; transcriptome sequencing

Defective skeletal patterning is a major contributor of congenital limb malformations, which are among the most frequent birth defects in humans. Loss of epigenetic regulation has been associated with several debilitating human disorders including immune and neurodevelopmental disorders among others. Aberrant DNA modifications either due to mutations in enzymes that catalyze the establishment, maintenance or the readers of these marks are intricately associated with human developmental disorders. Building on Dr. Kota’s previous training and experience in the fields of epigenetic regulation of monoallelic gene expression and stem cell biology, this K01 application will support advanced research training in the interdisciplinary areas of developmental skeletal biology and epigenomics which will enable him to become an independent investigator in the emerging multidisciplinary area of epigenetic regulation of developmental skeletal biology. Specifically, during the K01 award period, Dr. Kota will receive advanced training in 1) theoretical and practical aspects of skeletal development and homeostasis, 2) analysis of mouse models of skeletal disorders and 3) genomic analysis of early limb progenitor cells, from a team of mentors at Harvard University. Training will be completed via formal coursework, hands-on lab training, mentored research and regular attendance at seminars and workshops. Based on the PI's preliminary findings in the mice, the research will focus on elucidating the role of the epigenetic gene regulation during skeletal patterning and aims to evaluate the transcriptome, epigenetic modifications in skeletal progenitors. In summary, the overall goal of the proposal is to understand the epigenetic regulation and its key targets during embryonic skeletal development to get better insights into human congenital limb abnormalities that eventually will lead to better therapeutic avenues.

Defective骨骼模式是先天性肢体畸形的主要原因，这是人类最常见的出生缺陷之一。表观遗传调控的丧失与几种衰弱的人类疾病有关，包括免疫和神经发育障碍等。由于催化这些标记的建立、维持或读取器的酶突变引起的异常DNA修饰与人类发育障碍有着复杂的联系。基于Kota博士之前在单等位基因表达的表观遗传调控和干细胞生物学领域的培训和经验，这个K01应用程序将支持发育骨骼生物学和表观基因组学跨学科领域的高级研究培训，这将使他成为发育骨骼生物学表观遗传调控新兴多学科领域的独立研究者。具体来说，在K01奖励期间，Kota博士将接受来自哈佛大学导师团队的高级培训，内容包括：1)骨骼发育和体内平衡的理论和实践方面；2)骨骼疾病小鼠模型分析；3)早期肢体祖细胞基因组分析。培训将通过正式课程、动手实验培训、指导研究和定期参加研讨会和讲习班来完成。基于PI在小鼠中的初步发现，研究将重点阐明表观遗传基因调控在骨骼模式中的作用，并旨在评估骨骼祖细胞的转录组，表观遗传修饰。总之，该提案的总体目标是了解胚胎骨骼发育过程中的表观遗传调控及其关键靶点，以更好地了解人类先天性肢体异常，最终将导致更好的治疗途径。