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(申请人提供)：动脉粥样硬化是一种多因素的炎症性疾病，通常会默默发展几十年，并伴有不稳定的斑块，导致急性冠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来评估斑块易损性程度方面取得了长足的进步，但较低的灵敏度和有限的准确性限制了它们在精确诊断方面的应用。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CCR2结合基序(残基13-35)，设计了单核细胞靶向、多肽两亲性胶束(MPAM)。单核细胞靶向是斑块形成的早期标志之一，它是分泌MCP-1的内皮细胞的激活，通过其CCR2受体大量招募单核细胞。更重要的是，最近的研究报告说，单核细胞的流入在斑块的整个发展过程中持续存在，并且与动脉粥样硬化的程度成正比。初步研究证实，MPAM在体外具有生物功能，在体内具有生物相容性，并通过光学成像评估成功靶向ApoE基因敲除小鼠的动脉粥样硬化斑块。有了有希望的初步发现，在K99阶段，我将检验这样一个假设，即通过将Gd掺入MPAM，开发出一种组合的分子磁共振成像工具，通过与招募的单核细胞结合，为斑块进展提供一个定量的、非侵入性的体内检测系统。在R00阶段，我建议加入胶原酶-1，或金属蛋白酶-1(MMP1)，以减轻斑块破裂，并利用这些新型多功能胶束在小鼠易损斑块模型中。监测单核细胞上调和定位的能力将是可能的，我们的研究将为多肽两亲性胶束介导的分子标记库的治疗奠定基础。在这个奖项的K99阶段，我将得到先驱、两亲肽专家、芝加哥大学分子工程研究所创始主任Matthew Tirrell博士的指导。作为对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密切合作，如James Liao博士和Godfrey Getz博士，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保持一致。此外，杰出的核磁共振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培训不仅将大大增强我在研究的诊断和治疗应用方面的知识和经验，还将帮助我在一家顶级研究机构找到一个独立的研究职位，以完成该奖项的R00阶段，并为我的第一份R01申请提供初步支持。我的长期目标是成为生物材料设计领域的领导者，以应对心血管疾病方面的挑战。