In vivo glycan engineering at the cell-matrix interface to control stem cell fate

细胞-基质界面的体内聚糖工程控制干细胞命运

基本信息

批准号：
8955575
负责人：
Kamil Godula
金额：
$ 232.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Stem cells have the remarkable ability to develop into a range of functional cell types of the adult body that can be used to repair damaged or diseased tissues. Despite advances in achieving selective differentiation in the laboratory, controlling the fate of stem cells post-transplantation still remains an unsolved challenge and a significant obstacle to the use of stem cells as therapeutics. Stem cell specification during development is orchestrated by the concerted action of morphogens, such as growth factors, which initiate intracellular signaling cascades activating gene transcription. Glycans populating surfaces of stem cells play a key role in regulating the interactions of growth factors with their cognate receptors; however, their regulatory functions have been largely unexplored in the context of achieving selectivity in differentiation. The objective of the proposed projects is to create new techniques for manipulating glycan structures at the surface of stem cells to tune the association of endogenous growth factors at the cell-matrix interface in vivo. Two distinct approaches are proposed to achieve this goal. The first approach describes priming of the stem cell surface prior to transplantation with nanoscale glycomimetic materials with affinity for a growth factor of interest. Once the remodeled cells are delivered to a tissue, these materials will promote the association of the endogenous growth factor and activate signaling and differentiation. The second approach outlines the targeted delivery of these materials to the surface of stem cells in vivo concomitant with the inhibition of glycan production in these cells. This in situ remodeling will allow us to temporarily override native glycan signals at a critical junction to achieve selective activation of growth factor signaling and a desired differentiation outcome. This work will provide a novel solution to a key problem in the field of regenerative medicine and will open new opportunities for exploration of the rich biology of glycans for applications in stem cell technologies, tissue engineering and biomedicine.

描述（由申请人提供）：尽管在实验室中实现选择性分化、控制命运方面取得了进展，但干细胞具有发育成成人身体的一系列功能细胞类型的非凡能力，可用于修复受损或患病的组织。移植后干细胞的分化仍然是一个未解决的挑战，并且是使用干细胞作为治疗的一个重大障碍。发育过程中的干细胞规范是由形态发生素（例如启动细胞内信号传导的生长因子）的协同作用来协调的。干细胞表面的聚糖在调节生长因子与其同源受体的相互作用中发挥着关键作用；然而，在实现分化选择性的背景下，它们的调节功能在很大程度上尚未得到探索。该项目的目的是创造操纵干细胞表面聚糖结构的新技术，以调节体内细胞-基质界面上内源生长因子的关联，以实现这一目标。在移植之前用对感兴趣的生长因子具有亲和力的纳米级糖模拟材料对干细胞表面进行启动，一旦重塑的细胞被递送到组织，这些材料将第二种方法概述了将这些材料靶向递送到体内干细胞表面，同时抑制这些细胞中的聚糖产生，这种原位重塑将使我们能够实现这一目标。暂时覆盖关键连接处的天然聚糖信号，以实现生长因子信号传导的选择性激活和所需的分化结果，这项工作将为再生医学领域的关键问题提供新的解决方案，并将为探索再生医学开辟新的机会。丰富的聚糖生物学应用干细胞技术、组织工程和生物医学。

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）

Glycocalyx Remodeling with Glycopolymer-Based Proteoglycan Mimetics.

使用基于糖聚合物的蛋白聚糖模拟物进行糖萼重塑。

DOI：
10.1007/978-1-4939-3130-9_17
发表时间：
2016
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Huang,MiaL;Smith,RaymondAA;Trieger,GregW;Godula,Kamil
通讯作者：
Godula,Kamil

Biologically Derived Neoproteoglycans for Profiling Protein–Glycosaminoglycan Interactions

用于分析蛋白质与糖胺聚糖相互作用的生物衍生新蛋白聚糖

DOI：
10.1021/acschembio.2c00205
发表时间：
2022
期刊：
ACS Chemical Biology
影响因子：
4
作者：
Porell, Ryan N.;Follmar, Julianna L.;Purcell, Sean C.;Timm, Bryce;Laubach, Logan K.;Kozirovskiy, David;Thacker, Bryan E.;Glass, Charles A.;Gordts, Philip L.;Godula, Kamil
通讯作者：
Godula, Kamil

Glycocalyx Scaffolding to Control Cell Surface Glycan Displays.

DOI：
10.1002/cpch.40
发表时间：
2018-06
期刊：
Current protocols in chemical biology
影响因子：
0
作者：
Huang ML;Tota EM;Verespy S 3rd;Godula K
通讯作者：
Godula K

Following sugar patterns in search of galectin function.

遵循糖模式寻找半乳糖凝集素功能。

DOI：
10.1073/pnas.1801039115
发表时间：
2018
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Godula,Kamil
通讯作者：
Godula,Kamil

Stem Cell Microarrays for Assessing Growth Factor Signaling in Engineered Glycan Microenvironments.