Breaching the barrier with matrix biology.
突破基质生物学的障碍。
基本信息
- 批准号:10582940
- 负责人:
- 金额:$ 24.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAnimal ModelAstrocytesBackBasement membraneBiologicalBiological AssayBiological ProcessBiologyBlood VesselsBypassCell TherapyCell TransplantationCell-Matrix JunctionCellsCicatrixCollaborationsCre lox recombination systemDataDependovirusDepositionDevelopmentDyesEffectivenessEngineeringEngraftmentExcisionExtravasationEyeFoundationsFutureGene TransferGenesGeneticGoalsImmunologic SurveillanceIn VitroInner Limiting MembraneKnowledgeLabelLaboratoriesLamininMediatingMembraneMethodsMicrospheresMolecular StructureMovementMusNaturePenetrancePenetrationPhysiologicalPolymersProceduresProteinsPublishingReporterRetinaRetinal DiseasesSiteStem cell transplantTechniquesTestingTherapeutic InterventionTissuesTransfectionVertebral columnViralViral VectorVirusVirus IntegrationWild Type MouseWorkcell typeclinically relevantconditional knockoutdepolymerizationexperimental studygene therapygenetic approachhigh riskin vivoin vivo evaluationinfection rateintravitreal injectionmolecular rearrangementmouse modelnerve stem cellnovelpolymerizationpreventreconstitutionresponseretinal progenitor cellreverse geneticsstem cellssuccesstheoriestherapeutic genetool
项目摘要
Basement membranes (BMs) are non-cellular protein layers that simultaneously provide
parenchymal cell-attachment sites and also barriers between tissue compartments. The inner
limiting membrane (ILM) is a special BM that prevents movement into the retina from the
vitreous as such it is a formidable barrier to intravitreal viral-mediated gene transfer or stem cell
transplantation. Current methods to circumvent the ILM involve its physical or enzymatic
removal with limited effectiveness. The consequence has been that successful cell- and gene-
based therapies have targeted a subretinal approach, an effective approach for the outer retina,
but of extremely limited use for the inner retina. The goal of this exploratory project is to
manipulate the molecular structure of the ILM to promote integration of neural stem cells or viral
transfection. ILM formation is dependent on the deposition of laminins, particularly those
containing the β2 subunit. We propose two different manipulations of the laminin polymer
forming the backbone of the ILM: one, genetic and a second, employs a small biomolecule to
disrupt the laminin polymer.
Our first approach will be to remove genetically a key component of the ILM, Lamb2. Our
prior studies show this disrupts the sheet-like nature of the ILM. We will test if this molecular
rearrangement of the ILM renders these retinae more permeant to cell and virus entry. Second
approach will be to disrupt laminin polymerizing; netrins, small matrix molecules with laminin
homology, are known to disrupt laminin polymerization during normal development and in
experimental conditions. We will produce netrin-induced focal disruptions of the ILM and assay
for facilitated gene and cell integration.
We will perform our experiments, in vitro using organotypic cultures of retina as well as in
vivo murine models. The in vitro approach has the advantage that we can add back laminin and
reconstitute the ILM and thereby proving that laminin manipulation is the key step. The in vivo
approach is more clinically relevant. While in this exploratory project, we will use murine models
future successor applications could employ more clinically relevant animal models.
Together, the experiments in this project will assess the barrier that the ILM presents to
biologic-based engraftment therapies. They will determine if specifically disrupting the laminin
backbone is enough to promote engraftment. These experiments if successful will provide a
powerful tool to promote advanced matrix-based approach to manipulation of retinal BMs to
promote gene-based and cell-based therapeutics in the inner retinal disease.
基底膜(BMS)是一种非细胞蛋白质层,同时提供
实质细胞附着部位以及组织间隔之间的屏障。内心世界
限制膜(ILM)是一种特殊的BM,可以防止从视网膜进入视网膜
玻璃体本身对玻璃体内病毒介导的基因转移或干细胞是一个强大的障碍。
移植。目前规避ILM的方法包括物理的或酶的
除名效果有限。其结果是成功的细胞和基因-
基于治疗的目标是视网膜下入路,一种有效的视网膜外入路,
但对视网膜内部的使用极其有限。这个探索性项目的目标是
操纵ILM的分子结构以促进神经干细胞或病毒的整合
转染法。ILM的形成依赖于层粘连蛋白的沉积,特别是那些
含有β2亚单位。我们建议对层粘连蛋白聚合物进行两种不同的操作
形成ILM的主干:一种是遗传的,另一种是利用一个小的生物分子来
破坏层粘连蛋白聚合体。
我们的第一个方法将是从基因上移除ILM的关键组成部分Lamb2。我们的
先前的研究表明,这破坏了ILM的片状性质。我们将测试这个分子是否
ILM的重新排列使这些视网膜更有利于细胞和病毒的进入。第二
方法是扰乱层粘连蛋白的聚合;网状蛋白,具有层粘连蛋白的小基质分子
同源物,已知在正常发育过程中扰乱层粘连蛋白聚合
实验条件。我们将产生Netrin诱导的ILM的局灶性干扰并进行检测
以促进基因和细胞的整合。
我们将在体外进行实验,使用器官类型的视网膜培养物以及
活体小鼠模型。体外方法的优点是我们可以添加回层粘连蛋白和
重建内界膜,从而证明层粘连蛋白的操纵是关键步骤。活体内
入路更具有临床相关性。在这个探索性项目中,我们将使用小鼠模型
未来的后续应用可能会采用更多临床相关的动物模型。
总而言之,该项目中的实验将评估ILM提供的障碍
基于生物的植入疗法。他们将确定是否专门破坏了层粘连蛋白
有骨气就足以促进嫁接。这些实验如果成功,将提供一种
推广先进的基于基质的视网膜BMS操作方法的有力工具
在视网膜内层疾病中推广基于基因和基于细胞的治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WILLIAM J BRUNKEN其他文献
WILLIAM J BRUNKEN的其他文献
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{{ truncateString('WILLIAM J BRUNKEN', 18)}}的其他基金
Role of Extracellular Matrix in Retinal Development and Disease
细胞外基质在视网膜发育和疾病中的作用
- 批准号:
10330943 - 财政年份:2019
- 资助金额:
$ 24.45万 - 项目类别:
Role of Extracellular Matrix in Retinal Development and Disease
细胞外基质在视网膜发育和疾病中的作用
- 批准号:
8512409 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
Extracellular matrix in synapse formation in the CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
6929077 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
Role of Extracellular Matrix in Retinal Development and Disease
细胞外基质在视网膜发育和疾病中的作用
- 批准号:
7992716 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
EXTRACELLULAR MATRIX IN SYNAPSE FORMATION IN THE CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
6446640 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
EXTRACELLULAR MATRIX IN SYNAPSE FORMATION IN THE CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
6384826 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
STRUCTURE AND FUNCTION OF NON BASEMENT MEMBRANE LAMININS
非基底膜层粘连蛋白的结构和功能
- 批准号:
6499449 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
Extracellular matrix in synapse formation in the CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
7087782 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
Extracellular matrix in synapse formation in the CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
7251457 - 财政年份:2000
- 资助金额:
$ 24.45万 - 项目类别:
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