CAREER: Photoactivated miRNA delivery for modulation of human adipose stromal cell differentiation

MicroRNA(MiRNA)是一种天然存在于动植物组织中的非编码小RNA序列，是一种很有前途的技术，可以改善伤口愈合和组织修复过程的控制。当与成人干细胞/基质细胞(ASC)疗法相结合时，这些技术可能会导致一种新的再生医学范例。一些基于miRNA和其他潜在寡核苷酸的疗法已被证明具有强大的生物活性，但由于毒性和缺乏特异性作用，目前最先进的寡核苷酸递送技术在很大程度上与临床治疗不相容。该项目将解决对临床上相关的、安全和有效的miRNA递送系统的迫切需求，该递送系统提供对病变或受损组织部位的激活的时间和空间控制。作为主要目标，该项目将以ASC为模型系统，优化基于纳米颗粒(NP)的、光激活的miRNA递送系统(LAMD)，用于光激活的骨和血管形成的空间和时间调节。第二个目标是开发一种更具成本效益和更坚固的工艺，用于制造目标版本的基本LAMD系统。对提高产量和形态控制的制造工艺的研究将解决使用靶向颗粒开发疗法的一个关键限制。随着老龄化人口寿命的延长和活动水平的增加，我们预计出现骨科损伤的患者数量将大幅增加。尤其令人感兴趣的是骨骼疾病的解决方案，如骨不连和因磨损、癌症、创伤或关节置换而导致的无法愈合的临界大小的缺陷。开发一种基于纳米颗粒的光激活的miRNA递送系统，解决了传统miRNA递送载体的局限性，同时提供对活性的空间和时间控制，可能会对miRNA在再生医学中的应用产生革命性的影响。这个项目每年将为几个本科生和研究生提供直接支持，让他们作为研究学者参与这个项目。该项目为主修生物医学工程、化学和相关领域的学生提供了一个独特的跨学科机会，以建立纳米材料合成、干细胞生物学、光生物学和再生医学领域的基础知识和欣赏。该项目的外展部分将包括K-12、本科生和研究生教育活动。

1254281HayesModulation of cell and tissue function with microRNA (miRNA), which are small non-coding RNA sequences naturally found in animal and plant tissues, is a promising technique to improve the control of wound healing and tissue repair processes. When combined with adult stem/stromal cell (ASC) therapies these techniques may result in a new regenerative medicine paradigm. Several miRNA and other potential oligonucleotide based therapeutics have been demonstrated to posses potent bioactivity but current state-of-the-art oligonucleotide delivery techniques are largely incompatible with clinical therapies due to toxicity and lack of specific action. This project will address the critical need for a clinically relevant, safe and effective miRNA delivery system which provides temporal and spatial control of activation at the site of diseased or damaged tissue. As a primary objective the project will optimize, a nanoparticle (NP) based, light activated, miRNA delivery system (LAMD) for the light activated spatial and temporal regulation of bone and blood vessel formation using ASC as a model system. A secondary objective is the development of a more cost effective and robust processes for the fabrication of a targeted version of the basic LAMD system. Research into manufacturing processes with improved yields and morphological control will address a critical limitation to the development of therapies using targeted particles.With the lengthening life span and increasing activity levels of the aging population we expect to see a substantial increase in the number of patients presenting with orthopaedic injuries. Of particular interest are solutions to skeletal disorders, such as bone disunions and non-healing, critical sized defects caused by wear, cancers, trauma or as the result joint replacement. The development of a photoactivated, nanoparticle based, miRNA delivery system that addresses the limitations of traditional miRNA delivery vectors while providing for spatial and temporal control of activity could be transformative for miRNA use in regenerative medicine. This project will provide direct support for several undergraduate and graduate students per year to work on this project as research scholars. The project presents a unique and interdisciplinary opportunity for students majoring in biomedical engineering, chemistry and related fields to build fundamental knowledge and appreciation in the areas of nanomaterial synthesis, stem cell biology, photobiology and regenerative medicine. The outreach components of this project will include K-12, undergraduate and graduate education activities.