Enhancing Transgene Expression and Retention by Co-delivery of DNA Vectors with Modified Histones

基因疗法被认为是治疗多种疾病的潜在疗法，包括血友病、囊性纤维化、帕金森氏症、艾滋病、肝炎和心脏病。传统的基因传递方法目前缺乏许多研究、工业和/或临床应用所需的安全性、效率和持久性。了解如何创造和维持活跃的基因表达将对人类基因的传递和表达产生广泛的影响。这项提议的工作将使有效的基因治疗更接近现实，也将通过他们积极参与这项跨学科研究来培养和激励下一代科学家和工程师。该项目的长期目标是阐明转录状态的长期细胞记忆是如何产生和维持的，以推进需要调节转基因表达的研究、工业和基因治疗应用。具体的科学目标是：1)开发一种强大的策略，将转基因与促进活性转录的修饰组蛋白一起共递送；2)评估和提高转基因DNA上组装的染色质的蛋白表达。所建立的递送方法有望显著改善转基因DNA的摄取和控制表达，并与广泛的载体兼容。关于异源基因表达表观遗传系统设计的基本知识可能对所有真核生物基因表达系统具有深远的影响。例如，这种见解可以大大扩大人类基因治疗的范围和功效，从而治愈许多严重疾病。

Gene therapy has been offered as a potential cure for a wide range of diseases, including hemophilia, cystic fibrosis, Parkinson's, HIV, hepatitis, and heart disease. Conventional gene delivery approaches currently lack the safety, efficiency and durability required for many research, industrial and/or clinical applications. Understanding how to create and maintain active gene expression will have broad-ranging impacts on gene delivery and expression in humans. The proposed work will bring effective gene therapies closer to reality, and will also train and inspire the next generation of scientists and engineers through their active participation in this interdisciplinary research.The long-term objective of this project is to elucidate how long-term cellular memories of transcriptional states are created and maintained to advance research, industrial and gene therapy applications requiring regulated transgene expression. The specific scientific objectives are to 1) develop a robust strategy for co-delivering transgenes together with modified histone proteins promoting active transcription; and 2) evaluate and enhance protein expression from chromatin assembled on transgenic DNA. The established delivery approach is expected to significantly improve the uptake and controlled expression of transgenic DNA and to be compatible with a broad range of vectors. The fundamental kowledge gained regarding the design of epigenetic systems for heterologous gene expression could have profound implications for all eukaryotic gene expression systems. Such insight could, for example, significantly expand the scope and efficacy of human gene therapy, leading to cures for many serious diseases.