Nuclear Organization Dynamics Regulate 3-Dimensional Vasculogenesis

核组织动力学调节三维血管发生

基本信息

批准号：
7807561
负责人：
STEPHEN J WEISS
金额：
$ 50万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7807561
关键词：
3-Dimensional Actomyosin Address Adipocytes Architecture Area Binding Biomechanics Blood Vessels Blood capillaries Cell Nucleus Cell Shape Cell physiology Cells Chondrocytes Chromatin Competence Cues Cytoplasmic Protein Cytoskeleton Deposition Development Disease Endothelial Cells Environment Extracellular Matrix F-Actin Family Genetic Programming Genome Growth Factor Health Inflammation Integral Membrane Protein Intermediate Filaments Lamins Life Link Mechanics Microtubules Morphogenesis Normal Cell Nuclear Nuclear Envelope Nuclear Inner Membrane Nuclear Matrix Nuclear Outer Membrane Pathway interactions Phenotype Play Population Process Property Protein Family Proteolysis Research Design Role Signal Transduction Stem cells Structure The Sun Translational Research Tumor Cell Biology angiogenesis capillary cell type member neoplastic cell neovascularization novel programs public health relevance receptor response scaffold tumor growth vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge area (15) Translational Science and specific Challenge Topic, 15-CA-101: The Role of Cellular Architecture in Normal and Tumor Cell Biology. New blood vessels are formed throughout life by either vasculogenic or angiogenic processes. During neovessel development, endothelial cell responses to pro-angiogenic signals are governed by the structural and biophysical remodeling of the surrounding 3-dimensional extracellular matrix. However, the mechanisms by which matrix-derived cues are integrated with the growth factor-initiated genetic programs that underlie morphogenesis remain largely undefined. In preliminary studies, we have succeeded in identifying a novel regulatory axis wherein extracellular matrix remodeling regulates neovessel development by controlling nuclear architecture, chromatin organization, and transcriptional competence of the genome under 3- dimensional-specific conditions. Transduction of extracellular matrix -derived signals to the nucleus requires functional interactions between the cytoskeleton, actomyosin, generated mechanical tension and Klarsicht, ANC-1, Syne homology domain-containing cytoplasmic proteins which transmit signals to the lamin-rich nuclear scaffold via members of the SUN protein family. These findings outline a novel endothelial cell mechanotransduction program that governs vasculogenesis/angiogenesis by transmitting biophysical signals received from the dynamically remodeled 3-D extracellular matrix to the nuclear compartment. As such, we propose to; i) characterize nuclear organization dynamics during 3-D neovessel formation, ii) define the role of extracellular matrix remodeling as an upstream regulator of nuclear architecture and transcriptional machinery and iii) characterize the cytoskeletal/nesprin/SUN/lamin axis as the transduction pathway of extracellular matrix-derived cues to the nuclear compartment. Taken together, these studies are designed to characterize a novel mechanotransduction program wherein endothelial cells purposely reshape nuclear architecture and function to regulate vasculogenesis and angiogenesis. Further, as normal cell types - ranging from stem cells to chondrocytes and adipocytes - as well as neoplastic cell populations similarly reside within a dynamically remodeling extracellular matrix, we posit that the mechanistic processes outlined in this proposal will have broad implications for controlling cell functions in health and disease. Public Health Relevance: These studies are designed to characterize a novel mechanotransduction program wherein endothelial cells purposely reshape nuclear architecture and function to regulate vasculogenesis by relaying biophysical signals received from the dynamically remodeled 3-dimensional extracellular matrix to the nucleus.

描述（由申请人提供）：此申请涉及广泛的挑战领域（15）转化科学和特定挑战主题，15-CA-101：细胞结构在正常和肿瘤细胞生物学中的作用。新血管通过血管生成或血管生成过程形成。在Neovesel发育过程中，内皮细胞对促血管生成信号的反应受周围三维细胞外基质的结构和生物物理重塑的控制。但是，基质衍生的提示与生长因子引发的遗传程序的机制在很大程度上不确定。在初步研究中，我们成功地确定了一个新的调节轴，其中细胞外基质重塑通过控制3维特异性条件下基因组的核结构，染色质组织以及基因组的转录能力来调节新系统的发育。细胞外基质衍生的信号向细胞核的转导需要在细胞骨架，肌动蛋白，肌动蛋白，产生的机械张力和Klarsicht，ANC-1，Syne同源结构域的细胞质蛋白之间通过lamamin-ramin-ramin-coctaff of luamamin rimin rimin coffold the Sum protine note sum protine sum protine sum protine sumains of Suntoplast蛋白。这些发现概述了一种新型的内皮细胞机械转导计划，该程序通过传输从动态重塑的3-D 3-D细胞外基质到核室的生物物理信号来控制血管生成/血管生成。因此，我们建议； i）表征在3-D Neovesl形成过程中的核组织动力学，ii）将细胞外基质重塑作为核架构和转录机械的上游调节剂以及III的作用）表征了细胞骨架/nesprin/nesprin/nesprin/sun/lamin轴作为外部核心构成核心的转移途径，以供核心构图。综上所述，这些研究旨在表征一个新型的机械转导程序，其中内皮细胞故意重塑核结构和功能以调节血管生成和血管生成。此外，正常细胞类型（从干细胞到软骨细胞和脂肪细胞）以及肿瘤细胞种群类似地存在于动态重塑的细胞外基质中，我们认为，该建议中概述的机械过程对控制细胞在健康和疾病中的作用将具有广泛的含义。公共卫生相关性：这些研究旨在表征一个新型的机械转移程序，其中内皮细胞故意重塑核结构和功能，以通过将从动态重塑的3二维细胞外基质中接收到的生物物理信号来调节血管生成。