Epigenetic regulation of skeletal patterning and morphogenesis during development

骨骼图案缺陷是先天性肢体畸形的主要原因，先天性肢体畸形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。由于催化建立、维持或这些标记的读取器的酶的突变而引起的DNA异常修饰与人类发育障碍有着错综复杂的联系。基于Kota博士以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，K01的应用将支持发育骨骼生物学和表观基因组学交叉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的新兴多学科领域的独立研究员。具体地说，在K01颁奖期间，柯塔博士将接受哈佛大学导师团队的高级培训，内容包括1)骨骼发育和动态平衡的理论和实践方面，2)骨骼疾病小鼠模型的分析，3)早期肢体祖细胞的基因组分析。培训将通过正式课程作业、动手实验室培训、有指导的研究以及定期参加研讨会和讲习班来完成。基于PI在小鼠身上的初步发现，该研究将专注于阐明表观遗传基因调控在骨骼模式形成中的作用，并旨在评估转录组，即骨骼祖细胞的表观遗传修饰。总而言之，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节及其关键靶点，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。

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.