I-Corps: Self-assembling, protein-based contrast agent targeted to collagen Type 1

I-Corps：针对 1 型胶原蛋白的自组装蛋白质造影剂

• 批准号: 2230243
• 负责人: Jin Montclare
• 金额: $ 5万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2230243&HistoricalAwards=false
• 关键词: Corps; Self; assembling; protein; based

The broader impact/commercial potential of this I-Corps project is the development of a preclinical imaging agent for non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease worldwide, with some estimates placing its prevalence at 25-30% of the adult population in developed Western nations. Because NAFLD develops insidiously, it may be difficult to detect in its early stage, and diagnosis is often incidental. A hallmark of the disease is inflammation and progressive fibrotic collagen deposition in the liver, leading to liver failure. Although biopsy is the gold standard for diagnosis, it is invasive and, therefore, not preferable. The proposed noninvasive longitudinal imaging technology fulfils many of these testng needs. In addition, the exploration of self-assembling proteins as biomedical imaging agents may also be used for other targets such as kidney or lung diseases. This I-Corps project is based on the development of a self-assembling, protein-based contrast agent targeted to collagen type I for non-alcoholic fatty liver disease (NAFLD). The technology seek to improve noninvasive diagnosis and monitoring of NAFLD in vivo. The core technology, Type I collagen-binding thermoresponsive assembled protein or COL1-TRAP, is a recombinant protein amphiphile composed of a type I collagen binding peptide fused to a pentameric coiled-coil (C) domain and an intrinsically disordered elastin-like polypeptide (ELP) domain. COL1-TRAP forms hierarchical, multimeric micelles at room temperature. These micelles are distinguished by their reversible self-assembly and disassembly in solution, forming a versatile class of stimuli-responsive materials with diverse applications. Recombinantly expressed protein micelles are of particular interest due to their hierarchical folding and potential for multivalent targeted interactions with binding ligands. The multimeric self-assembled structure means that a relatively short binding sequence with a moderate affinity for collagen may be used, with the combination of weak interactions summing to a high affinity interaction. The result is a targeted, high affinity smart binder for collagen type I. Tracking of collagen type I deposition may help visualize the fibrosis across the liver as NAFLD progresses. In addition, the proposed technology may form the basis for more sensitive and effective noninvasive imaging agents.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该I-Corps项目的更广泛的影响/商业潜力是开发非酒精性脂肪肝病（NAFLD）的临床前成像剂。 NAFLD是全球最常见的慢性肝病，其中一些估计将其流行率占发达国家的成年人口的25-30％。因为NAFLD在阴险的情况下发展，因此在早期阶段可能很难检测到，并且诊断通常是偶然的。该疾病的标志是肝脏炎症和进行性纤维化胶原蛋白沉积，导致肝衰竭。尽管活检是诊断的黄金标准，但它具有侵入性，因此不是可取的。提出的非侵入性纵向成像技术满足了许多这些测试需求。 此外，将自组装蛋白作为生物医学成像剂的探索也可以用于其他靶标，例如肾脏或肺部疾病。该I-Corps项目基于针对非酒精脂肪肝疾病（NAFLD）的胶原蛋白I型的自组装，基于蛋白质的对比剂的发展。 该技术旨在改善体内NAFLD的无创诊断和监测。核心技术是I型胶原结合的热重质组装蛋白或COL1捕获，是一种重组蛋白两亲的重组，由I型I胶原蛋白结合肽组成，融合到五聚体串联螺旋（C）结构域和内在无序的弹性蛋白蛋白样的多肽（Elppeptide（Elp）域）。 Col1陷阱在室温下形成分层的多聚胶束。这些胶束的区别是它们可逆的自组装和溶液中的拆卸，形成具有多种应用的多功能刺激反应材料。重组表达的蛋白胶束特别感兴趣，因为它们的分层折叠以及与结合配体的多价靶向相互作用的潜力。多聚体自组装结构意味着，可以使用具有适度亲和力的相对较短的结合序列，将弱相互作用求和到高亲和力相互作用的组合结合在一起。结果是针对I型胶原蛋白的有针对性的高亲和力智能粘合剂。胶原蛋白I型沉积的跟踪可能会随着NAFLD的进展，可视化肝脏的纤维化。此外，提出的技术可能构成了更敏感和有效的非侵入性成像代理的基础。该奖项反映了NSF的法定任务，并且使用基金会的知识分子优点和更广泛的影响评估标准，认为值得通过评估来获得支持。