NeoProteoglycans as synthetic materials for regenerative medicine and bioimaging

新蛋白聚糖作为再生医学和生物成像的合成材料

• 批准号: 8091489
• 负责人: Kamil Godula
• 金额: $ 8.23万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091489
• 关键词: Affect; Alzheimer' s Disease; Amyloid fibers; Anabolism; Architecture; Area; Atomic Force Microscopy; Award; Binding; Biochemical; Biocompatible Materials; Biological; Biological Process; Biology; Biomechanics; Biomedical Research; Bone Tissue; Carbohydrates; Cartilage; Cell Surface Receptors; Cell physiology; Cells; Cellular biology; Chemicals; Chemistry; Collaborations; Communities; Complex; Crystallization; Cues; Data; Decision Making; Development; Dimensions; Engineering; Environment; Event; Extracellular Matrix; Faculty; Fluorescence; Fostering; Future; Glycosaminoglycans; Goals; Growth; Growth Factor; Health; Heterogeneity; Homeostasis; Hydroxyapatites; Image; In Situ; Inorganic Sulfates; Interdisciplinary Study; Laboratories; Laboratory Research; Lead; Libraries; Life; Ligands; Malignant Neoplasms; Medical; Membrane Glycoproteins; Mentors; Mentorship; Methodology; Methods; Molecular; Molecular Biology; Molecular Biology Techniques; Molecular Structure; Muscle; Nanostructures; Neuromuscular Junction; Organism; Osteogenesis; Phase; Polymers; Polysaccharides; Positioning Attribute; Postdoctoral Fellow; Property; Protein Engineering; Proteins; Proteoglycan; Regenerative Medicine; Research; Research Project Grants; Research Proposals; Resistance; Resolution; Resources; Role; Running; Science; Scientist; Screening for cancer; Screening procedure; Signal Pathway; Signal Transduction; Specificity; Structure; Sulfatases; Surface; Techniques; Technology; Time; Tissue Engineering; Tissues; Training; Translating; Tumor Tissue; Tumor-Associated Process; Universities; Unspecified or Sulfate Ion Sulfates; Vertebral column; Water; Work; bioimaging; biomineralization; calcification; cancer cell; carbohydrate binding protein; career; career development; chemical reaction; college; density; design; experience; forging; frontier; instrumentation; member; mimetics; molecular recognition; nanocomposite; nanocrystal; nanoimaging; nanomaterials; nanometer; nanoscale; nanoscience; neglect; nerve supply; neurogenesis; novel; novel diagnostics; novel therapeutics; planetary Atmosphere; programs; rapid technique; scaffold; skills; stem cell differentiation; sulfation; tissue regeneration; tissue support frame; tool; tumor

DESCRIPTION (provided by applicant): My career goal is to lead an interdisciplinary research program at a major US university, which will combine components of nanomaterials, tissue engineering, and bioimaging research to create new therapeutic and diagnostic tools. This K99/R00 application has two components that will help me achieve my goal: 1) At the research level, it outlines a strategy for the development of functional nanoscale mimetics of proteoglycans, a class of cellular function regulators, and their integration into a microarray discovery platform to generate materials for biomedical use. 2) The training portion of this application describes the steps I will take to acquire the necessary skills in molecular and cell biology, nanoimaging, and professional and career development I will need to build such an interdisciplinary research program and launch a successful career as an independent scientist and scholar. The R00 award will provide an important start-up support for my team, while we establish the research projects outlined in this application. The preliminary data we will generate with the help of this award will be vital as we seek future research support. Background: My academic and research experience makes me well positioned to develop the cross- disciplinary research program outlined in this application. My graduate research focused on the development of new chemical reactions and the application of these transformations in the construction of complex organic molecules. As a postdoctoral fellow, I have used my synthetic skills to create a new class of nanoscale mimetics of cell-surface glycoproteins for microarray applications. During this work, I became familiar with carbohydrate and polymer synthesis, microarray fabrication, and a number of methods for surface and soft nanomaterials characterization. In addition, I have helped establish and run a synthetic laboratory at the Molecular Foundry, gaining an invaluable experience for the future, when I start my own research laboratory. Research: The attached research proposal outlines the design of nanoscale surrogates of proteoglycans (which I term "neoPGs") and their use as cellular function modulators in tissue engineering scaffolds, as imaging agents for early cancer detection, and as novel macromolecular templates for nanocrystal growth and nanocomposites assembly. Proteoglycans perform all these functions in living organisms; however, harnessing their unique capabilities for medical purposes has so far proved challenging. Their structural complexity, compositional and functional heterogeneity, and non-template biosynthesis limits their applicability in biomedical research. My proposal outlines a simple synthetic strategy that translates the basic architectural features responsible for proteoglycans' biological function into nanoscale polymeric neoPGs. Taking advantage of the technological power of microarrays, and my skills in building them, my team will construct a "neoPG chip", to rapidly interrogate a library of neoPG structures for their ability to exert desirable biological properties. In three specific projects, we will demonstrate neoPGs' broad utility and their potential for biomedical research. Training: The K99 training component of this award will be critical during my transition to the independent phase of my academic career. The biomedical focus of the research I intend to pursue necessitates that I become proficient in the topics and techniques of molecular and cell biology. The proposed training under the mentorship of Prof. Bertozzi will help me attain these skills. The nanoimaging techniques I will acquire through collaboration with Dr. James De Yoreo at the Molecular Foundry will enable my research team to design materials that match the dimensions of biological building blocks and explore new ways to engineer biological interfaces. The numerous professional and career development resources available through LBNL and UC Berkeley and my stellar mentoring committee assembled from experts in molecular biology, biomaterials, nanoscience, and tissue engineering will be an invaluable asset, while I seek a faculty position in the US and as I launch my own independent career. Environment: As a member of the Bertozzi lab, I will have access to the state-of-the-art facilities at the Molecular Foundry and the resources and instrumentation of UC Berkeley's College of Chemistry. The scientific excellence and diversity of the Bertozzi research team, its well-established record of high-impact contributions to the fields of chemical and molecular biology, and the highly collaborative atmosphere Prof. Bertozzi fosters in her group will facilitate my rapid progress in molecular and cell biology training. Collaboration with Dr. James DeYoreo at the Molecular Foundry and the expertise of the Foundry's scientific staff will provide an important support, as I undertake my training in nanomaterials imaging and characterization. Finally, UC Berkeley's renowned academic and scientific community provides a vibrant environment, in which to exchange ideas, forge collaborations, and explore new frontiers in science and will undoubtedly contribute to my professional growth.

描述(由申请人提供)：我的职业目标是在美国一所主要大学领导一个跨学科的研究项目，该项目将结合纳米材料、组织工程和生物成像研究的组成部分，创造新的治疗和诊断工具。这个K99/R00应用程序有两个组件将帮助我实现我的目标：1)在研究层面，它概述了开发蛋白多糖的功能纳米级模拟的战略，以及将它们集成到微阵列发现平台中以产生生物医学使用的材料。2)本申请的培训部分描述了我将采取的步骤，以获得在分子和细胞生物学、纳米成像以及职业和职业发展方面的必要技能，以建立这样一个跨学科研究计划，并作为一名独立科学家和学者开始成功的职业生涯。R00奖将为我的团队提供重要的创业支持，同时我们将建立本申请中概述的研究项目。在我们寻求未来研究支持时，我们将在该奖项的帮助下产生的初步数据将是至关重要的。背景：我的学术和研究经验使我能够很好地开发这份申请中列出的跨学科研究计划。我的研究生研究重点是新的化学反应的发展和这些转化在构建复杂有机分子中的应用。作为一名博士后，我使用我的合成技能为微阵列应用创造了一类新的纳米级细胞表面糖蛋白模拟物。在这项工作中，我熟悉了碳水化合物和聚合物的合成，微阵列的制作，以及一些表面和软纳米材料表征的方法。此外，我还帮助在分子铸造厂建立和运营了一个合成实验室，为未来我开始自己的研究实验室积累了宝贵的经验。研究：所附研究建议书概述了蛋白质多聚糖纳米级替代物(我称之为“新PG”)的设计，以及它们在组织工程支架中作为细胞功能调节剂、作为早期癌症检测的成像剂以及作为纳米晶体生长和纳米复合材料组装的新型大分子模板的用途。蛋白多糖在活体中执行所有这些功能；然而，到目前为止，将其独特的能力用于医疗目的是具有挑战性的。它们的结构复杂性、组成和功能的异质性以及非模板生物合成限制了它们在生物医学研究中的应用。我的提案概述了一种简单的合成策略，它将蛋白多糖生物学功能的基本结构特征转化为纳米级的聚合新PG。利用微阵列的技术力量和我建造它们的技能，我的团队将构建一个“新PG芯片”，以快速询问新PG结构的库，以了解它们发挥理想生物特性的能力。在三个具体的项目中，我们将展示新前列腺素的广泛用途及其在生物医学研究中的潜力。培训：该奖项的K99培训部分在我向学术生涯的独立阶段过渡期间将是至关重要的。我打算从事的研究的生物医学重点要求我精通分子和细胞生物学的主题和技术。在贝尔托齐教授的指导下拟议的培训将帮助我获得这些技能。我将通过与詹姆斯·德·约雷奥博士在分子铸造厂的合作获得纳米成像技术，这将使我的研究团队能够设计出与生物构件尺寸匹配的材料，并探索设计生物界面的新方法。LBNL和加州大学伯克利分校提供的大量专业和职业发展资源，以及我由分子生物学、生物材料、纳米科学和组织工程专家组成的优秀指导委员会，将是一笔无价的财富，而我正在寻找美国的教员职位，并开始我自己的独立职业生涯。环境：作为Bertozzi实验室的一员，我将有机会接触到分子铸造的最先进的设施以及加州大学伯克利分校化学学院的资源和仪器。Bertozzi研究团队在科学上的卓越和多样性，其在化学和分子生物学领域做出重大贡献的良好记录，以及Bertozzi教授在她的团队中培养的高度合作的氛围，将促进我在分子和细胞生物学培训方面的快速进步。在分子铸造厂与James DeYoreo博士的合作以及铸造厂科学工作人员的专业知识将为我提供重要的支持，因为我正在接受纳米材料成像和表征方面的培训。最后，加州大学伯克利分校著名的学术和科学社区提供了一个充满活力的环境，在其中交流思想，建立合作，探索科学的新领域，这无疑将有助于我的职业成长。