Mimicking, Exploiting, and Understanding Biology's Heterogeneity in 4D

在 4D 中模仿、利用和理解生物学的异质性

• 批准号: 10028017
• 负责人: Cole A DeForest
• 金额: $ 37.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028017
• 关键词: 3-Dimensional; Animal Model; Area; Biochemical; Biocompatible Materials; Biological Markers; Biological Process; Biology; Blood Vessels; Blood capillaries; Cardiovascular system; Cell Culture Techniques; Cell physiology; Cells; Cues; Development; Disease; Disease Progression; Drug resistance; Endothelium; Event; Exhibits; Foundations; Hematological Disease; Heterogeneity; Homeostasis; Human; Hydrogels; In Vitro; Knowledge; Life; Logic; Malignant Neoplasms; Methodology; Methods; Morphogenesis; Optics; Organ; Photochemistry; Physiological; Prevention; Process; Proteins; Proteomics; Reporting; Research; Resolution; Sickle Cell Anemia; Signal Transduction; Signaling Protein; Specificity; Therapeutic; Thrombosis; Time; Tissue Banks; Tissue Model; Tissues; Universities; Visualization; Washington; base; biophysical properties; disease diagnosis; drug action; in vivo; migration; multidisciplinary; nanoparticle; new therapeutic target; programs; response; small molecule; spatiotemporal; tool; tumor

PROJECT SUMMARY Our bodies consist of an exquisite collection of tissues and organs that undergo constant change. From morphogenesis and homeostasis to the progression of disease, these changes are associated with both the healthy and unhealthy processes that define human life. My research program at the University of Washington is developing robust and uniquely powerful multidisciplinary methodologies to mimic, exploit, and quantify these changes, particularly as they evolve in both time and 3D space (i.e., 4D). In our lab’s first five years of existence, we have: (1) developed a suite of synthetic cell-culture platforms whose biochemical and biophysical properties can be reversibly modulated in 4D using cytocompatible photochemistries, and have utilized these platforms to regulate proliferation, migration, differentiation, and intracellular signaling at single- and sub-cellular resolutions; (2) introduced a photodegradable material-based approach to generate the first endothelialized 3D vascular networks within cell-laden hydrogel biomaterials that span nearly all size scales of native human vasculature (including capillaries); (3) reported the first modular framework for imparting biomaterials with precise degradative responsiveness to multiple environmental cues/biomarkers following user-programmable Boolean logic; and (4) established the first tools for “spatiotemporally resolved proteomics”, enabling visualization and quantification of proteins produced in vitro and in vivo within user- defined regions in 4D. The present proposal expands our group’s capabilities in each of these areas, paving the way to new therapeutic targets and treatments of disease through a fundamentally transformed knowledge of basic cell physiology. In this project, we will: (1) exploit our 4D-tunable biomaterials to recapitulate and probe cardiovascular developmental signaling in vitro, examining the manner in which precise spatial and temporal presentation of signaling proteins culminates in orchestrated differentiation; (2) employ synthetic capillaries to examine drug action and resistance, screen therapeutics, and investigate microvascular occlusion, thrombosis, and altered remodeling that occurs in many hematologic diseases (e.g., sickle cell anemia, spherocytosis); (3) develop and deploy hydrogel nanoparticles exhibiting logic-based degradative response to cancer-presented biomarkers to deliver small molecule chemotherapeutics to tumors with unprecedented specificity; and (4) extend our 4D proteomic strategies to permit optically and physiologically defined proteomic mapping in living tissue and model organisms. Critically, the methods that we are developing and implementing are cell-, tissue-, and disease-agnostic, enabling enhanced understanding of a wide variety of biological processes while laying the foundation for advances in disease diagnosis, treatment, and prevention.

项目摘要 我们的身体由一系列精致的组织和器官组成，这些组织和器官不断发生变化。从 形态发生和稳态的疾病进展，这些变化都与这两个 健康和不健康的过程来定义人类的生活。我在华盛顿大学的研究项目 正在开发强大而独特的多学科方法来模拟，利用和量化 这些变化，特别是当它们在时间和3D空间两者中演变时（即，4D）。在我们实验室的前五年里， 存在，我们已经：（1）开发了一套合成细胞培养平台，其生化和 生物物理性质可以使用细胞相容性光化学在4D中可逆地调节，并且具有 利用这些平台来调节增殖、迁移、分化和细胞内信号传导， 和亚细胞分辨率;（2）引入了一种基于光降解材料的方法来生成第一个 在载有细胞的水凝胶生物材料内的内皮化3D血管网络，其跨越几乎所有的尺寸尺度， 天然人体血管系统（包括毛细血管）;（3）报道了第一个模块化框架，用于赋予 生物材料对多种环境线索/生物标志物具有精确的降解反应性， 用户可编程布尔逻辑;（4）建立了第一个“时空分辨”工具 蛋白质组学”，使可视化和定量的蛋白质产生的体外和体内的用户- 在4D中定义区域。目前的建议扩大了我们集团在这些领域的能力， 通过从根本上改变知识， 基本的细胞生理学。在这个项目中，我们将：（1）利用我们的4D可调生物材料来重现和探测 心血管发育信号在体外，检查的方式，精确的空间和时间 信号蛋白的呈递在协调分化中达到高潮;（2）采用合成毛细血管， 检查药物作用和耐药性，筛选治疗方法，并研究微血管闭塞，血栓形成， 以及在许多血液病中发生的改变的重塑（例如，镰状细胞性贫血，球形红细胞增多症）;（3） 开发和部署水凝胶纳米颗粒，其对癌症呈现的 生物标志物，以前所未有的特异性将小分子化学治疗剂递送至肿瘤;以及（4） 扩展我们的4D蛋白质组学策略，以允许在生活中光学和生理学定义的蛋白质组学图谱 组织和模式生物。重要的是，我们正在开发和实施的方法是细胞，组织， 和疾病不可知论，使人们能够在奠定基础的同时加强对各种生物过程的理解， 疾病诊断、治疗和预防的基础。