Multimodal Peptide Amphiphile Micelles for Atherosclerosis

用于治疗动脉粥样硬化的多模式肽两亲胶束

• 批准号: 9321402
• 负责人: Eun Ji Chung
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321402
• 关键词: Address; Angiotensin II; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Award; Binding; Biochemical Markers; Biocompatible Materials; Biodistribution; Biological; Biological Assay; Biology; Cardiovascular Diseases; Cardiovascular system; Chemicals; Chicago; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Elements; Endothelial Cells; Engineering; Ensure; Epitopes; Event; Fatty acid glycerol esters; Gadolinium; Goals; Half-Life; Hand; Heart Arrest; High Fat Diet; Histology; Hydrophobicity; Imaging Device; Imaging technology; Immunohistochemistry; In Vitro; Inflammatory; Infusion procedures; Injectable; Institutes; Interstitial Collagenase; Investigation; Knockout Mice; Knowledge; Label; Libraries; Link; Magnetic Resonance Imaging; Measures; Mediating; Medicine; Mentors; Metalloproteases; Micelles; Molecular; Molecular Bank; Monitor; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Mus; Penetration; Peptides; Phase; Positioning Attribute; Preventive measure; Property; Recruitment Activity; Reporting; Research; Research Institute; Research Personnel; Resolution; Rupture; Scientist; Site; Smooth Muscle Myocytes; Source; Specificity; System; Tail; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Training; Translations; Universities; Up-Regulation; Water; Work; accurate diagnosis; acute coronary syndrome; aqueous; biomaterial compatibility; chemokine receptor; clinical application; clinically relevant; collagenase; collagenase 1; combinatorial; design; experience; imaging agent; in vitro activity; in vivo; in vivo imaging; molecular diagnostics; molecular imaging; molecular marker; monocyte; monocyte chemoattractant protein 1 receptor; mortality; mouse model; multimodality; nanoparticle; novel; novel diagnostics; novel therapeutic intervention; optical imaging; protein aminoacid sequence; public health relevance; targeted imaging; theranostics; tool

 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.

 描述（由适用提供）：抽象的动脉粥样硬化是一种多因素的炎症性疾病，通常会静静地发展数十年，并且由于不稳定的斑块而变得复杂，导致急性冠状动脉综合征和突然心脏骤停。尽管当前的成像技术已取得了长足的进步，以分配物理和结构参数，以评估斑块脆弱性，敏感性差和准确性有限的程度限制了其对精确诊断的效用。下一个挑战是实时成像斑块的分子事件，以确定牙菌斑进展的程度。为此，我们最近通过掺入单核细胞化学吸收剂蛋白-1（MCP-1）的趋化因子受体CCR2结合基序（残基13-35）（MCP-1）的趋化因子受体CCR2结合基序（残基13-35）（MCP-1），通过掺入趋化因子受体CCR2结合基序（残基13-35）（MCP-1）。单核细胞的靶向是高度可取的，因为牙菌斑形成的早期标记之一是秘密MCP-1的内皮细胞的激活，通过其CCR2受体大量募集单核细胞。更重要的是，最近的研究报告了单核细胞的影响在整个斑块进展过程中一直持续，并且与动脉粥样硬化的程度成正比。初步研究已经证实了MPAM在体外的生物功能，体内生物相容性以及通过光学成像评估的APOE敲除小鼠中的动脉粥样硬化斑块的成功靶向。在有承诺的初步发现中，在K99阶段，我将测试以下假设：通过将gadolinium掺入MPAM的组合，分子MR成像工具的发展，通过与新型的单一单子镜结合结合斑块进行斑块进展。在R00阶段，我提出了胶原酶1或金属蛋白酶-1（MMP-1）的掺入，裂解位点以减弱斑块破裂以及这些小说的利用，多功能胶束在易受伤害牌匾的鼠模型中。可以可能监测单核细胞的上调和定位的能力，我们的研究将为肽两亲胶束胶束介导的疗法提供分子标记库的疗法。在该奖项的K99阶段中，我将被芝加哥大学Matthew Tirrell博士的先锋先生专家兼肽两亲专家兼创始主任。补充了Tirrell博士的指导，我将与世界一流的心血管临床医生和科学家（例如James Liao博士和Godfrey Getz博士）紧密合作，他们将确保我的进步与对心血管生物学和医学产生相关影响。此外，杰出的MRI研究员和临床，Brian Roman博士和Seon-Kyu Lee博士将指导我的体内成像设计。我的K99培训不仅将在我的研究的诊断和治疗应用中大大增强我的知识和经验，而且还将成为帮助在顶级研究所找到独立研究职位的工具，以完成该奖项的R00阶段，并为我的第一个R01应用提供初步支持。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。