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

基本信息

项目摘要

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(申请人提供):在美国,心肌和外周组织的缺血是导致心力衰竭和组织坏死的主要原因。缺血性疾病的临床治疗是通过给药和手术来进行的,但在永久治疗方面仍然面临许多挑战。近年来,通过血管生成和/或血管生成重建缺血组织血管网络的血运重建疗法被广泛研究,以恢复各种组织的血液灌流。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联合使用有望成为血管重建药物。这些细胞通常通过冠状动脉内注射进行移植,但由于缺乏引导细胞到达受损内皮细胞的信号,移植细胞的治疗效果会因细胞的显著损失而大大降低。这项研究的目的是开发一种纳米级的细胞导向分子,并将其附着到移植细胞上,使移植细胞能够定位受损的内皮细胞,从而改善缺血组织的血液灌注量。我们假设,与移植细胞结合的表位和与血管细胞黏附分子(VCAM)-1结合的表位连接的超支化聚甘油将准确地将移植细胞引导到损伤的内皮,因为内皮损伤刺激内皮细胞过度表达VACM-1。最终,这种细胞导向的调整将显著改善缺血组织中血液灌流的恢复。我们将使用来自猪脐带血的内皮祖细胞(EPC)来检验这一假说。含有RGD序列的寡肽(RGD肽)将被用作EPC结合表位,而含有VHSPNKK序列的寡肽(VHSPNKK肽)将被用作VCAM1结合表位。寡肽结构将发生变化,以提高与细胞和VCAM-1的结合亲和力。这两个寡肽将在化学上连接到聚甘油。通过体外分析进一步优化聚甘油低聚肽的取代程度。具体地说,我们将使用我们之前开发的荧光共振能量转移(FRET)技术来量化与内皮祖细胞结合的聚甘油的数量。我们将完成这项拟议的研究,首先用RGD多肽对聚甘油进行功能化处理[RGD-聚甘油]并分析聚甘油与内皮祖细胞的结合数量(目标1),然后用VHSPNKK多肽[RGD-聚甘油-VHSPNKK]修饰RGD-聚甘油并分析其引导内皮祖细胞进入合成内皮的能力(目标2),最后利用免疫缺陷小鼠肢体缺血(目标3)证明生物活性聚甘油的功能(目标3)。这项研究将通过组织工程师(孔,研究员)、化学家(齐默尔曼)和生物学家(舒克)之间的跨学科合作进行。Kong和Zimmerman的团队负责生物活性聚甘油的合成,并在体外和体内评估其增强移植细胞与目标缺血组织的粘附性的能力。Shook小组将对脐带血中的细胞分离和鉴定进行评估。我们相信,这项拟议研究的成功完成将显著减少移植细胞的损失,并提高内皮祖细胞修复缺血组织的治疗能力。我们的体外和体内研究结果将很容易转化为大规模的临床前和临床试验,并有助于基于细胞的新生血管治疗进入临床环境。最后,这种细胞导向系统的设计策略以及与细胞和靶组织的分子结合的定量分析将广泛适用于广泛的干细胞和祖细胞阵列,用于治疗许多疾病。 公共卫生相关性:这项拟议研究的成功完成将创建一个精确的细胞引导系统,该系统将极大地提高治疗细胞的再生效率,并加快细胞在缺血性疾病临床治疗中的使用。具体地说,通过对细胞导向系统的体外和体内分析,将加快将这项研究的结果转化为临床试验。最终,这项研究将有助于挽救一些患有心肌和外周组织缺血性疾病的患者。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Engineering the Surface of Therapeutic "Living" Cells.
  • DOI:
    10.1021/acs.chemrev.7b00157
  • 发表时间:
    2018-02-28
  • 期刊:
  • 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:
  • 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:
  • 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:
  • 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:
  • 影响因子:
    0
  • 作者:
    Zill,Andrew;Rutz,AlexandraL;Kohman,RichieE;Alkilany,AlaaldinM;Murphy,CatherineJ;Kong,Hyunjoon;Zimmerman,StevenC
  • 通讯作者:
    Zimmerman,StevenC
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Hyunjoon Kong其他文献

Hyunjoon Kong的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Hyunjoon Kong', 18)}}的其他基金

Self-Locomotive Antimicrobial Micro-Robot (SLAM) Enhancing Biofilm-Infected Wound Healing
自移动抗菌微型机器人 (SLAM) 增强生物膜感染伤口愈合
  • 批准号:
    10366359
  • 财政年份:
    2022
  • 资助金额:
    $ 19.04万
  • 项目类别:
Self-Locomotive Antimicrobial Micro-Robot (SLAM) Enhancing Biofilm-Infected Wound Healing
自移动抗菌微型机器人 (SLAM) 增强生物膜感染伤口愈合
  • 批准号:
    10612835
  • 财政年份:
    2022
  • 资助金额:
    $ 19.04万
  • 项目类别:
Modular Assembly of 3T (Targeting, Tracking and Treating) Nanocells for Vascular
用于血管的 3T(靶向、跟踪和治疗)纳米细胞的模块化组装
  • 批准号:
    8161467
  • 财政年份:
    2011
  • 资助金额:
    $ 19.04万
  • 项目类别:
Nanocells for vascular normalization therapies
用于血管正常化治疗的纳米细胞
  • 批准号:
    8306701
  • 财政年份:
    2011
  • 资助金额:
    $ 19.04万
  • 项目类别:
Nanocells for vascular normalization therapies
用于血管正常化治疗的纳米细胞
  • 批准号:
    8461633
  • 财政年份:
    2011
  • 资助金额:
    $ 19.04万
  • 项目类别:
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:
    7713070
  • 财政年份:
    2009
  • 资助金额:
    $ 19.04万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 19.04万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了