CAREER: Assembly of Nanopieces for Controlled Penetration and Binding of Difficult-to-Reach Cartilage Matrix for siRNA Therapy against Osteoarthritis

职业：组装纳米片，用于控制穿透和结合难以到达的软骨基质，用于骨关节炎的 siRNA 治疗

• 批准号: 1905785
• 负责人: Yupeng Chen
• 金额: $ 48.06万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1905785&HistoricalAwards=false
• 关键词: CAREER; Assembly; Nanopieces; Controlled; Penetration

PI: Chen, YupengProposal #: 1653702Osteoarthritis (OA) affects approximately 13.9% of Americans aged 25 years and older. This equates to an estimated 30 million people in the United States, making it one of the leading causes of disability. OA is a degenerative joint disease involving in the degeneration of joint cartilage. This leads to pain, stiffness, movement problems, and activity limitations. Currently, there is no clinically successful therapeutic to against OA. As a Nobel-prize winning discovery, siRNA can effectively and specifically inhibit disease gene expression, which provides a great therapeutic potential to treat OA. However, it is extremely challenging to deliver negatively-charged siRNAs to infiltrate avascular, dense, negatively-charged tissue matrix, such as cartilage. This research will develop a novel delivery vehicle, which can self-assemble with therapeutic siRNAs and deliver them into matrix-rich tissues in an effective and safe manner. The proposed study will focus on understanding the delicate self-assembly process between rosette nanotubes (RNTs) and siRNA into non-covalent architectures. By mediating the assembly process, the RNT/siRNA architectures will be constructed into siRNA delivery vehicles of various sizes and shapes. Then, their ability to penetrate tissue matrix and deliver siRNA will be analyzed and optimized. This proposal will also identify and manipulate the binding ability of these non-covalent delivery vehicles with tissue matrix molecules to achieve effective and long-lasting inhibition of matrix metalloproteinase-13 (MMP-13), a key disease gene during OA progression. Furthermore, the therapeutic potential of this siRNA approach against OA will be evaluated in an animal model. In addition, this proposal provides a plan to merge the gap between science and medical education and train the next generation of scientists and clinicians with interdisciplinary knowledge and encourage them to translate science, engineering and technology innovations to satisfy clinical needs. Lastly, collaborating with the Barrington High School (BHS) in Rhode Island, this proposal will develop an outreach plan to introduce nanotechnology to high school students and demonstrate to them how it can help overcome "real-life problems" in clinics. Beyond achieving the specific goals of this proposal, this career development plan can significantly improve scientific understanding of the self-assembly of non-covalent structures as well as lay the foundation for the development of the first siRNA therapy to inhibit OA progression.

PI：Chen，Yupeng提案编号：1653702骨关节炎 (OA) 影响大约 13.9% 的 25 岁及以上美国人。这相当于美国估计有 3000 万人，使其成为残疾的主要原因之一。 OA是一种涉及关节软骨退化的退行性关节疾病。这会导致疼痛、僵硬、运动问题和活动限制。目前，临床上尚无成功的针对 OA 的治疗方法。作为一项获得诺贝尔奖的发现，siRNA可以有效、特异性地抑制疾病基因表达，这为治疗OA提供了巨大的治疗潜力。然而，递送带负电荷的 siRNA 来渗透无血管、致密、带负电荷的组织基质（例如软骨）是极具挑战性的。这项研究将开发一种新型递送载体，它可以与治疗性 siRNA 自组装，并以有效、安全的方式将其递送到富含基质的组织中。 拟议的研究将重点了解玫瑰花结纳米管 (RNT) 和 siRNA 之间微妙的自组装过程，形成非共价结构。通过介导组装过程，RNT/siRNA 架构将被构建成各种尺寸和形状的 siRNA 递送载体。然后，将分析和优化它们穿透组织基质和递送 siRNA 的能力。该提案还将鉴定和操纵这些非共价递送载体与组织基质分子的结合能力，以实现对基质金属蛋白酶-13（MMP-13）（OA进展过程中的关键疾病基因）的有效和持久的抑制。此外，还将在动物模型中评估这种 siRNA 方法针对 OA 的治疗潜力。此外，该提案还提出了一项计划，旨在弥合科学与医学教育之间的差距，培养具有跨学科知识的下一代科学家和临床医生，并鼓励他们转化科学、工程和技术创新，以满足临床需求。最后，该提案将与罗德岛州巴灵顿高中（BHS）合作，制定一项外展计划，向高中生介绍纳米技术，并向他们展示纳米技术如何帮助克服诊所中的“现实生活问题”。除了实现该提案的具体目标之外，该职业发展计划还可以显着提高对非共价结构自组装的科学理解，并为开发第一个抑制 OA 进展的 siRNA 疗法奠定基础。

项目成果

Blood-brain-barrier modeling with tissue chips for research applications in space and on Earth

• DOI: 10.3389/frspt.2023.1176943
• 发表时间: 2023-08-09
• 期刊: FRONTIERS IN SPACE TECHNOLOGIES
• 作者: Yau，Anne;Jogdand，Aditi;Chen，Yupeng
• 通讯作者: Chen，Yupeng

A biomimetic layer-by-layer drug-released Nano-Matrix for mesenchymal stem cells chondrogenic differentiation promotion and chondrocytes hypertrophy prevention

仿生层层释药纳米基质促进间充质干细胞软骨分化和预防软骨细胞肥大

• 发表时间: 2021
• 期刊: Trans Orthop Res Soc.
• 作者: Zhou, L.

A structural and functional comparison between two recombinant human lubricin proteins: Recombinant human proteoglycan-4 (rhPRG4) vs ECF843

两种重组人润滑素蛋白之间的结构和功能比较：重组人蛋白聚糖 4 (rhPRG4) 与 ECF843

• DOI: 10.1016/j.exer.2023.109643
• 发表时间: 2023
• 期刊: Experimental Eye Research
• 影响因子: 3.4
• 作者: Menon, Nikhil G.;Tanguay, Adam P.;Zhou, Libo;Zhang, Ling X.;Bobst, Cedric E.;Han, Mingyu;Ghosh, Mallika;Greene, George W.;Deymier, Alix;Sullivan, Benjamin D.
• 通讯作者: Sullivan, Benjamin D.

Anti-Cancer Drug Delivery via DNA-Inspired Janus Base Nanotubes

通过 DNA 启发的 Janus 基础纳米管进行抗癌药物输送

• 发表时间: 2020
• 期刊: Trans Orthop Res Soc
• 作者: Zhang, W;Shen, Z;Chen, Y.
• 通讯作者: Chen, Y.

Janus Base Derived Nanopieces for Delivery of Anti-miRNA Oligonucleotides in Chondrosarcoma.

Janus 碱衍生的纳米片用于在软骨肉瘤中递送抗 miRNA 寡核苷酸。

• 发表时间: 2019
• 期刊: Trans Orthop Res Soc.
• 作者: R. M. Terek, X. Sun