Multimodal Peptide Amphiphile Micelles for Atherosclerosis

 描述（由申请人提供）：摘要动脉粥样硬化是一种多因素的炎性疾病，通常在数十年内悄无声息地进展，并伴有不稳定斑块，导致急性冠状动脉综合征和心脏骤停。尽管目前的成像技术在分配物理和结构参数以评估斑块脆弱性程度方面取得了很大进展，但灵敏度低和准确性有限限制了其用于精确诊断的实用性。下一个挑战是实时成像斑块的分子事件，以确定斑块进展的程度。为此，我们最近通过掺入单核细胞趋化蛋白-1（MCP-1）的趋化因子受体CCR 2结合基序（残基13-35）来设计单核细胞靶向肽两亲胶束（MPAMs）。单核细胞靶向是高度期望的，因为斑块形成的早期标志物之一是分泌MCP-1的内皮细胞的活化，通过它们的CCR 2受体大量募集单核细胞。更重要的是，最近的研究报告单核细胞的流入持续整个斑块进展，并与动脉粥样硬化的程度成正比。初步研究已经证实了MPAM的体外生物功能性、体内生物相容性以及通过光学成像评估的ApoE敲除小鼠中动脉粥样硬化斑块的成功靶向。在K99阶段，我将测试的假设，即结合钆MPAM的组合，分子MR成像工具的发展提供了一个定量的，非侵入性的，在体内检测系统的斑块进展结合招募的单核细胞。在R 00阶段，我建议纳入胶原酶-1，或金属蛋白酶-1（MMP-1），裂解位点，以减少斑块破裂和利用这些小说，多功能胶束在小鼠模型的脆弱斑块。监测单核细胞的上调和定位的能力将是可能的，我们的研究将为肽两亲性胶束介导的分子标记物库的治疗诊断奠定基础。在这个奖项的K99阶段，我将由先驱，肽两亲物专家和芝加哥大学分子工程研究所的创始主任Matthew Tirrell博士指导。作为Tirrell博士指导的补充，我将与世界一流的心血管临床医生和科学家（如James Liao博士和戈弗雷Getz博士）密切合作，他们将确保我的进展与心血管生物学和医学的相关影响保持一致。此外，杰出的MRI研究人员和临床医生Brian Roman博士和Seon-Kyu Lee博士将指导我的体内成像设计。我的K99培训不仅将大大提高我的知识和经验与诊断和治疗应用我的研究，但也将是一个工具，以帮助找到一个独立的研究职位在一个顶级研究机构完成该奖项的R 00阶段，并提供初步的支持，以准备我的第一个R 01申请。我的长期目标是成为生物材料设计的领导者，以应对心血管疾病的挑战。

 DESCRIPTION (provided by applicant): ABSTRACT Atherosclerosis is a multifactorial, inflammatory disease that often progresses silently for decades and is complicated by unstable plaques that result in acute coronary syndromes and sudden cardiac arrest. Although current imaging technologies have made great strides to assign physical and structural parameters to assess the degree of plaque vulnerability, poor sensitivity and limited accuracy restrict their utility for precise diagnosis. The next challenge is to image molecular events of a plaque in real-time to determine the extent of plaque progression. To this end, we have recently engineered monocyte-targeting, peptide amphiphile micelles (MPAMs) through the incorporation of the chemokine receptor CCR2-binding motif (residues 13-35) of the monocyte chemoattractant protein-1 (MCP-1). Monocyte targeting is highly desirable as one of the early markers of plaque formation is the activation of endothelial cells which secrete MCP-1, recruiting monocytes in large quantities through their CCR2 receptor. More importantly, recent studies report the influx of monocytes continues throughout plaque progression and is proportional to the extent of atherosclerosis. Preliminary studies have confirmed biofunctionality of MPAMs in vitro, biocompatibility in vivo, and successful targeting to atherosclerotic plaques in ApoE knock-out mice assessed via optical imaging. With promising preliminary findings in hand, in the K99 phase, I will test the hypothesis that the development of a combinatorial, molecular-MR imaging tool by incorporating gadolinium to MPAMs provides a quantitative, noninvasive, in vivo detection system for plaque progression by binding to recruited monocytes. In the R00 phase, I propose the incorporation of the collagenase-1, or metalloproteinase-1 (MMP-1), cleavage site to attenuate plaque rupture and the utilization of these novels, multifunctional micelles in a murine model of vulnerable plaque. The ability to monitor the upregulation and the localization of monocytes will be possible and our investigations will lay the ground work for peptide amphihphile micelle-mediated theranostics for a library of molecular markers. In the K99 phase of this award, I will be mentored by the pioneer, peptide amphiphile expert and founding director of the Institute for Molecular Engineering at the University of Chicago, Dr. Matthew Tirrell. Supplemental to Dr. Tirrell's guidance, I will work closely with world-class cardiovascular clinicians and scientists such as Dr. James Liao and Dr. Godfrey Getz, who will ensure my progress aligns with making a relevant impact on cardiovascular biology and medicine. Furthermore, outstanding MRI researcher and clinician, Dr. Brian Roman and Dr. Seon-Kyu Lee, will guide my design for in vivo imaging. My K99 training will not only substantially enhance my knowledge and experience with diagnostic and therapeutic applications of my research, but will also be a vehicle to help locate an independent research position at a top research institute to complete the R00 phase of this award, and provide the initial support to prepare for my first R01 application. My long term goal is to become a leader in biomaterial design to tackle the challenges in cardiovascular disease.