Modulation of Signal Transduction by Nano-Topography

纳米形貌调制信号转导

• 批准号: 7922386
• 负责人: CHRISTOPHER John MURPHY
• 金额: $ 40.92万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922386
• 关键词: Address; Adhesions; Adhesives; Advanced Development; Affect; Architecture; Basement membrane; Behavior; Binding; Biological Assay; Biomechanics; Cell Adhesion Molecules; Cell Proliferation; Cell membrane; Cells; Cellular biology; Characteristics; Complex; Cornea; Cues; Data; Development; Dimensions; Elements; Engineering; Epithelial Cells; Event; Family; Figs - dietary; Focal Adhesions; Guanosine Triphosphate Phosphohydrolases; Integrins; Intervention; Laboratories; Length; MAP Kinase Gene; MAPK14 gene; Maintenance; Mediating; Nanotopography; PTK2 gene; Pathway interactions; Pattern; Phosphorylation; Phosphotransferases; Play; Prosthesis; RNA Interference; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Silicon; Subgroup; Surface; Testing; Time; Tissue Engineering; Tissues; Western Blotting; Width; Work; cell behavior; corneal epithelium; density; gene therapy; member; migration; nanoscale; novel strategies; receptor; response; rho; submicron; syndecan; synthetic polymer Bioplex; time use

DESCRIPTION: A fundamental question in cell biology is how surface topography regulates cell behavior. Our previous and ongoing work has focused on defining the topography of native basement membranes and determining the "phenotypic impact" of biologically relevant length scales on modulating corneal epithelial cell behaviors. Using silicon surfaces patterned with grooves and ridges, we have shown that biologic length scale topographic features modulate corneal epithelial cell orientation, adhesion, migration and proliferation. Topography also influences the architecture and orientation of focal adhesions as well as the distribution and orientation of cytoskeletal elements within the cell. Importantly, we have demonstrated that a transition in the cellular response to topography for many behaviors occurs at approx. 1,200 nm pitch (pitch = ridge + groove width) with the greatest impact of topography generally occurring in the nanoscale range, the range of feature sizes found in the native basement membrane. It is possible that the observed effects are caused directly (e.g. biomechanical transduction events initiated at the cell membrane) and/or indirectly (e.g. the topography of the substratum dictates the density and/or distribution of adhesion complexes which in turn modulate cell behaviors). Preliminary data support the central hypothesis that nanoscale (1-100 nm) and submicron (< 1 mu m) topographic features of the substratum, characteristic of those found in the native corneal basement membranes, constrain focal contact architecture resulting in altered signaling and cellular responses. These studies have relevance to our fundamental understanding of the role that topographic cues play in the normal development and maintenance of the corneal epithelium. Furthermore, data generated will contribute to the genesis of novel strategies in tissue engineering and advance the development of ocular prosthetics. We have assembled a strong interdisciplinary team of senior investigators to test the following hypotheses: Hypothesis 1: Integrins and syndecans mediate cellular responses to topographic cues. Hypothesis 2: The scale of topographic features modulates the activity of the Ras superfamily of GTPases. Hypothesis 3: The scale of topographic features modulates matrix receptor kinase targets that, in turn, modulate cell behaviors.

描述：细胞生物学的一个基本问题是表面形貌如何调节细胞行为。我们之前和正在进行的工作重点是定义天然基底膜的形貌，并确定生物学相关长度尺度对调节角膜上皮细胞行为的“表型影响”。使用带有凹槽和脊图案的硅表面，我们已经证明生物长度尺度的地形特征调节角膜上皮细胞的方向、粘附、迁移和增殖。地形还影响粘着斑的结构和方向以及细胞内细胞骨架元素的分布和方向。重要的是，我们已经证明，细胞对许多行为的地形反应的转变发生在大约。 1,200 nm 间距（间距 = 脊 + 凹槽宽度）对地形影响最大，通常发生在纳米级范围内，即天然基底膜中发现的特征尺寸范围。观察到的效应可能是直接引起的（例如在细胞膜上引发的生物力学转导事件）和/或间接引起的（例如基质的形貌决定了粘附复合物的密度和/或分布，进而调节细胞行为）。初步数据支持中心假设，即基底的纳米级（1-100 nm）和亚微米（< 1 μm）地形特征（天然角膜基底膜中发现的特征）限制焦点接触结构，导致信号传导和细胞反应改变。这些研究与我们对地形线索在角膜上皮的正常发育和维护中所起的作用的基本理解相关。此外，生成的数据将有助于组织工程新策略的产生，并推动眼假体的发展。我们组建了一支由高级研究人员组成的强大跨学科团队来测试以下假设： 假设 1：整合素和多配体介导细胞对地形线索的反应。假设 2：地形特征的规模调节 GTPases Ras 超家族的活性。假设 3：地形特征的规模调节基质受体激酶靶点，进而调节细胞行为。