Nano-sized Cell Guidance System for Ischemic Tissue Repair

用于修复缺血组织的纳米细胞引导系统

• 批准号: 7898525
• 负责人: Hyunjoon Kong
• 金额: $ 19.04万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898525
• 关键词: Adhesions; Affinity; Amputation; Atherosclerosis; Binding; Blood Vessels; CUL5 gene; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Cell Separation; Cell Transplantation; Cell Transplants; Cells; Chronic Disease; Clinical; Clinical Treatment; Clinical Trials; Disease; Endothelial Cells; Endothelium; Epitopes; Evaluation; Expeditions; Family suidae; Fluorescence Resonance Energy Transfer; Glycerol; Goals; Growth; Growth Factor; Heart failure; Hindlimb; Immunodeficient Mouse; In Vitro; Inflammatory; Injection of therapeutic agent; Injury; Ischemia; Limb structure; Link; Medicine; Molecular Analysis; Myocardial; Necrosis; Oligopeptides; Operative Surgical Procedures; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Poly (RGD); RGD (sequence); Research; Research Personnel; Signal Transduction; Stem cells; Stroke; Structure; System; Techniques; Therapeutic; Thromboembolism; Tissue Engineering; Tissues; Translating; Translations; Transplantation; Treatment Efficacy; Umbilical Cord Blood; United States; Vascular Cell Adhesion Molecule-1; Wound Healing; angiogenesis; base; blood perfusion; cytokine; design; improved; in vivo; injured; interdisciplinary collaboration; meetings; nanosized; neovascularization; pre-clinical; public health relevance; regenerative; repaired; restoration; stem; vasculogenesis

DESCRIPTION (provided by applicant): Ischemia in myocardial and peripheral tissues is a leading cause of heart failure and tissue necrosis in the United States. Ischemic diseases are clinically treated with drug administration and surgery, which still meet many challenges for treatment on a permanent basis. Recently, revascularization therapy to rebuild the vascular network of ischemic tissue via angiogenesis, vasculogenesis or both is being extensively studied to restore blood perfusion in various tissues. A variety of stem and progenitor cells are promising revascularization medicines in conjunction with several angiogenic cytokines and growth factors. Commonly, these cells are transplanted via intracoronary injection, but the therapeutic efficacy of transplanted cells is greatly reduced by a significant loss of cells due to the absence of the signals to guide the cells to the injured endothelium. The objectives of this proposed study are to develop a nano-sized cell guidance molecule and attach it to the transplanted cells, so the transplanted cells can pinpoint the injured endothelium and subsequently improve blood perfusion of ischemic tissue. We hypothesize that a hyper-branched poly(glycerol) linked with both epitopes binding with transplanted cells and those binding with vascular cell adhesion molecules (VCAM)-1 will precisely guide transplanted cells to the injured endothelium because the endothelial injury stimulates endothelial cells to over-express VACM-1. Ultimately, this tuning of cell guidance will significantly improve restoration of blood perfusion in the ischemic tissue. We will examine this hypothesis using endothelial progenitor cells (EPCs) derived from a porcine cord blood. The oligopeptide containing RGD sequence (RGD peptide) will be used as the EPC-binding epitope and that containing VHSPNKK sequence (VHSPNKK peptide) will be used as the VCAM1- binding epitope. The oligopeptide structure will be varied to improve the binding affinity to cells and VCAM-1. These two oligopeptides will be chemically linked to the poly(glycerol). The degree of oligopeptides substitution to poly(glycerol) will be further optimized with in vitro analysis. Specifically, we will use a fluorescence resonance energy transfer (FRET) technique we previously developed to quantify the number of poly(glycerol) bound to EPCs. We will complete this proposed study by first functionalizing poly(glycerol) with RGD peptides [RGD- poly(glycerol)] and analyzing the amount of poly(glycerol) bound with EPCs (Aim 1), secondly modifying RGD-poly(glycerol) with VHSPNKK peptides [RGD-poly(glycerol)-VHSPNKK] and analyzing its ability to guide EPCs to the synthetic endothelium (Aim 2) and finally demonstrate the function of bioactive poly(glycerol) in vivo using the immunodeficient mouse with an ischemic hindlimb (Aim 3). This study will be performed through the interdisciplinary collaboration between a tissue engineer (Kong, investigator), chemist (Zimmerman) and biologist (Schook). Kong and Zimmerman's groups are responsible for the synthesis of bioactive poly(glycerol) and evaluation of its ability to enhance the transplanted cell adhesion to the target ischemic tissue in vitro and in vivo. The cell isolation from a cord blood and characterization will be evaluated by the Schook group. We believe that the successful completion of this proposed study will significantly minimize the loss of transplanted cells and improve the therapeutic potency of EPCs for repairing ischemic tissue. Results from our in vitro and in vivo studies will be readily translated into the large scale preclinical and clinical trials, and aid the expedition of cell-based neovascularization therapies to the clinical setting. Finally, this design strategy of a cell guidance system and quantitative analysis of the molecular binding with cells and target tissue will be widely applicable to a broad array of stem and progenitor cells for the treatment of many diseases. PUBLIC HEALTH RELEVANCE: The successful completion of this proposed study will create a precision cell guidance system that will greatly improve the regenerative efficacy of therapeutic cells and expedite the use of cells in clinical treatment of ischemic disease. Specifically, the through in vitro and in vivo analysis of cell guidance system will expedite the translation of the results of this study into the clinical trials. In the end, this study will aid saving a number of patients who suffer from the ischemic disorders of myocardial and peripheral tissues.

描述（由申请人提供）：心肌和周围组织中的缺血是美国心力衰竭和组织坏死的主要原因。缺血性疾病在临床上接受药物管理和手术治疗，这些疾病仍然面临许多永久治疗挑战。最近，通过血管生成，血管生成或两者进行了血管生成治疗，以重建缺血组织的血管网络，以恢复各种组织中的血液灌注。各种干细胞和祖细胞与几种血管生成细胞因子和生长因子结合使用了血运重建药物。通常，这些细胞是通过冠状体内注射移植的，但是由于缺乏信号引导细胞引导细胞到受伤的内皮细胞，因此细胞的显着损失大大降低了移植细胞的治疗功效。这项拟议的研究的目的是开发纳米尺寸的细胞引导分子并将其连接到移植细胞上，因此移植的细胞可以确定损伤的内皮细胞并随后改善缺血性组织的血液灌注。我们假设一个与移植细胞结合的表位和与血管细胞粘附分子（VCAM）-1结合的表位相关的超支线聚（甘油）将精确地引导与受伤的内皮细胞移植细胞，因为内皮损伤会刺激内皮损伤对内皮损伤的过度表达的空间。最终，这种细胞引导的调整将显着改善缺血组织中血液灌注的恢复。我们将使用源自猪脊血液的内皮祖细胞（EPC）检查这一假设。含有RGD序列的寡肽（RGD肽）将用作EPC结合表位，并将包含VHSPNKK序列（VHSPNKK肽）用作VCAM1-结合表位。寡肽结构将变化以改善与细胞和VCAM-1的结合亲和力。这两种寡肽将与聚甘油（甘油）化学联系。通过体外分析，将进一步优化将寡肽的寡肽替代程度。具体而言，我们将使用先前开发的荧光共振能量传递（FRET）技术来量化与EPC结合的聚（甘油）的数量。 We will complete this proposed study by first functionalizing poly(glycerol) with RGD peptides [RGD- poly(glycerol)] and analyzing the amount of poly(glycerol) bound with EPCs (Aim 1), secondly modifying RGD-poly(glycerol) with VHSPNKK peptides [RGD-poly(glycerol)-VHSPNKK] and analyzing its ability to guide EPC到合成的内皮（AIM 2），最后证明了使用缺血后肢的免疫缺陷小鼠体内生物活性聚（甘油）的功能（AIM 3）。这项研究将通过组织工程师（Kong，研究人员），化学家（Zimmerman）和生物学家（Schook）之间的跨学科合作进行。 Kong和Zimmerman的群体负责生物活性聚（甘油）的合成，并评估其增强移植细胞粘附在体外和体内对靶缺血性组织的能力。从脐带血和表征中分离的细胞分离将由Schook组评估。我们认为，这项提出的研究的成功完成将显着最大程度地减少移植细胞的丧失，并提高EPC修复缺血组织的治疗效力。我们的体外和体内研究的结果将很容易转化为大规模的临床前和临床试验，并有助于将基于细胞的新生血管化疗法探险到临床环境。最后，这种细胞引导系统的设计策略以及与细胞和靶组织结合的分子结合的定量分析将广泛适用于多种茎和祖细胞，以治疗许多疾病。 公共卫生相关性：这项拟议的研究的成功完成将创建一个精确的细胞引导系统，该系统将大大提高治疗细胞的再生疗效，并加快细胞在缺血性疾病的临床治疗中使用。具体而言，细胞引导系统的通过体外和体内分析将加快将本研究结果转化为临床试验。最后，这项研究将有助于节省许多患有心肌和周围组织缺血性疾病的患者。

项目成果

Engineering the Surface of Therapeutic "Living" Cells.

• DOI: 10.1021/acs.chemrev.7b00157
• 发表时间: 2018-02-28
• 期刊: Chemical reviews
• 影响因子: 62.1
• 作者: Park J;Andrade B;Seo Y;Kim MJ;Zimmerman SC;Kong H
• 通讯作者: Kong H

Tuning the non-equilibrium state of a drug-encapsulated poly(ethylene glycol) hydrogel for stem and progenitor cell mobilization.

• DOI: 10.1016/j.biomaterials.2010.11.021
• 发表时间: 2011-03
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Liang, Youyun;Jensen, Tor W.;Roy, Edward J.;Cha, Chaenyung;DeVolder, Ross J.;Kohman, Richie E.;Zhang, Bao Zhong;Textor, Kyle B.;Rund, Lauretta A.;Schook, Lawrence B.;Tong, Yen Wah;Kong, Hyunjoon
• 通讯作者: Kong, Hyunjoon

Tuning hydrogel properties and function using substituent effects.

• DOI: 10.1039/c001548b
• 发表时间: 2010-01-01
• 期刊: Soft matter
• 影响因子: 3.4
• 作者: Kohman RE;Cha C;Zimmerman SC;Kong H
• 通讯作者: Kong H

Shear-Resistant, Biological Tethering of Nanostimulators for Enhanced Therapeutic Cell Paracrine Factor Secretion.

• DOI: 10.1021/acsami.1c01520
• 发表时间: 2021-04-21
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Hong, Yu-Tong;Teo, Jye Yng;Jeon, Hojeong;Kong, Hyunjoon
• 通讯作者: Kong, Hyunjoon

Clickable polyglycerol hyperbranched polymers and their application to gold nanoparticles and acid-labile nanocarriers.

可点击的聚甘油超支化聚合物及其在金纳米粒子和酸不稳定纳米载体中的应用。

• DOI: 10.1039/c0cc04096g
• 发表时间: 2011
• 期刊: Chemical communications (Cambridge, England)
• 作者: Zill,Andrew;Rutz,AlexandraL;Kohman,RichieE;Alkilany,AlaaldinM;Murphy,CatherineJ;Kong,Hyunjoon;Zimmerman,StevenC
• 通讯作者: Zimmerman,StevenC