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/商业潜力是开发一种治疗非酒精性脂肪性肝病(NAFLD)的临床前显像剂。NAFLD是世界上最常见的慢性肝病，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发病潜伏，早期可能难以发现，诊断往往是偶然的。该病的一个特征是炎症和进行性纤维化的胶原沉积，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，因此并不可取。提出的非侵入性纵向成像技术满足了许多测试需求。此外，自组装蛋白作为生物医学显像剂的探索也可能用于其他靶点，如肾脏或肺部疾病。这个I-Corps项目是基于一种以I型胶原蛋白为目标的自组装蛋白质造影剂的开发，用于治疗非酒精性脂肪性肝病(NAFLD)。该技术旨在提高NAFLD的非侵入性诊断和活体监测。核心技术，I型胶原结合热反应组装蛋白或COL1-TRAP，是由I型胶原结合多肽融合到五聚体卷曲(C)结构域和固有无序的弹性蛋白样多肽(ELP)结构域组成的重组蛋白两亲性。Col1陷阱在室温下形成分层的多聚体胶束。这些胶束的独特之处在于它们在溶液中的可逆自组装和分解，形成了一类用途广泛的刺激响应材料。重组表达的蛋白质胶束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而特别令人感兴趣。多聚体自组装结构意味着可以使用对胶原具有中等亲和力的相对较短的结合序列，弱相互作用的组合总和为高亲和力相互作用。其结果是一种靶向的、高亲和力的I型胶原智能结合剂。跟踪I型胶原的沉积可能有助于随着NAFLD的进展而可视化整个肝脏的纤维化。此外，拟议的技术可能成为更敏感和更有效的非侵入性成像代理的基础。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.