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

这个I-Corps项目的更广泛的影响/商业潜力是开发非酒精性脂肪性肝病（NAFLD）的临床前成像剂。 NAFLD是全球最常见的慢性肝病，据估计，在西方发达国家，其患病率为成年人口的25-30%。由于NAFLD的发展是隐蔽的，因此在早期阶段可能很难检测到，诊断往往是偶然的。该疾病的一个标志是肝脏中的炎症和进行性纤维化胶原沉积，导致肝功能衰竭。虽然活检是诊断的金标准，但它是侵入性的，因此不是首选。所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，探索自组装蛋白质作为生物医学成像剂也可用于其他目标，如肾脏或肺部疾病。该I-Corps项目基于开发一种自组装、基于蛋白质的造影剂，针对I型胶原蛋白，用于治疗非酒精性脂肪肝（NAFLD）。 该技术旨在改善体内NAFLD的非侵入性诊断和监测。核心技术，I型胶原结合热响应组装蛋白或COL 1-TRAP，是由I型胶原结合肽融合到五聚体卷曲螺旋（C）结构域和内在无序弹性蛋白样多肽（ELP）结构域组成的重组蛋白两亲物。COL 1-TRAP在室温下形成分级的多聚体胶束。这些胶束的特点是它们在溶液中可逆的自组装和分解，形成了一类用途广泛的刺激响应材料。由于其分层折叠和与结合配体的多价靶向相互作用的潜力，特异性表达的蛋白质胶束特别令人感兴趣。多聚体自组装结构意味着可以使用对胶原蛋白具有中等亲和力的相对短的结合序列，其中弱相互作用的组合总计为高亲和力相互作用。结果是针对I型胶原蛋白的靶向高亲和力智能结合剂。 跟踪I型胶原沉积可能有助于可视化NAFLD进展时肝脏的纤维化。此外，拟议的技术可能形成更敏感和更有效的非侵入性成像agents.This奖项反映了NSF的法定使命的基础，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.