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）：本申请涉及广泛的挑战领域 (15) 转化科学和具体挑战主题，15-CA-101：细胞结构在正常和肿瘤细胞生物学中的作用。新血管在整个生命过程中通过血管生成或血管生成过程形成。在新血管发育过程中，内皮细胞对促血管生成信号的反应受到周围 3 维细胞外基质的结构和生物物理重塑的控制。然而，基质衍生的线索与构成形态发生的生长因子启动的遗传程序整合的机制在很大程度上仍不清楚。在初步研究中，我们已经成功地确定了一个新的调控轴，其中细胞外基质重塑通过在3维特定条件下控制基因组的核结构、染色质组织和转录能力来调节新血管的发育。细胞外基质来源的信号向细胞核的转导需要细胞骨架、肌动球蛋白、产生的机械张力和含有 Klarsicht、ANC-1、Syne 同源结构域的细胞质蛋白之间的功能性相互作用，这些蛋白通过SUN 蛋白家族。这些发现概述了一种新颖的内皮细胞机械转导程序，该程序通过将从动态重塑的 3-D 细胞外基质接收到的生物物理信号传输到核区室来控制血管生成/血管生成。因此，我们建议； i) 表征 3-D 新生血管形成过程中的核组织动力学，ii) 定义细胞外基质重塑作为核结构和转录机制上游调节器的作用，以及 iii) 表征细胞骨架/nesprin/SUN/核纤层蛋白轴作为细胞外基质衍生的核区室信号。总而言之，这些研究旨在描述一种新颖的机械转导程序，其中内皮细胞有目的地重塑核结构和功能以调节血管生成和血管生成。此外，由于正常细胞类型（从干细胞到软骨细胞和脂肪细胞）以及肿瘤细胞群同样存在于动态重塑的细胞外基质中，因此我们认为该提议中概述的机制过程将对控制细胞功能产生广泛的影响。健康和疾病。公共健康相关性：这些研究旨在描述一种新颖的机械转导程序，其中内皮细胞通过将从动态重塑的 3 维细胞外基质接收到的生物物理信号传递到细胞核，有目的地重塑核结构和调节血管生成的功能。