Nuclear Organization Dynamics Regulate 3-Dimensional Vasculogenesis

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，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。在新生血管发育过程中，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。然而，基质来源的线索整合与生长因子启动的遗传程序的基础形态发生的机制仍然在很大程度上不确定。在初步研究中，我们已经成功地确定了一种新的调节轴，其中细胞外基质重塑调节新生血管的发展，通过控制核结构，染色质组织，和转录能力的基因组在三维特定条件下。将细胞外基质衍生的信号转导至细胞核需要细胞骨架、肌动球蛋白、产生的机械张力和Klarsicht、ANC-1、含有Syne同源结构域的细胞质蛋白之间的功能性相互作用，所述细胞质蛋白通过SUN蛋白家族的成员将信号传递至富含核纤层蛋白的核支架。这些研究结果概述了一种新的内皮细胞mechanotransduction程序，通过将从动态重塑的3-D细胞外基质接收的生物物理信号传输到核室来管理血管发生/血管生成。因此，我们建议：i）表征3-D新血管形成期间的核组织动力学，ii）定义细胞外基质重塑作为核结构和转录机制的上游调节剂的作用，和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线索到核隔室的转导途径。总之，这些研究旨在表征一种新的机械转导程序，其中内皮细胞有目的地重塑核结构和功能，以调节血管发生和血管生成。此外，由于正常细胞类型-从干细胞到软骨细胞和脂肪细胞-以及肿瘤细胞群体类似地存在于动态重塑的细胞外基质中，我们认为本提案中概述的机制过程将对控制健康和疾病中的细胞功能具有广泛的影响。 公共卫生相关性：这些研究旨在表征一种新的机械转导程序，其中内皮细胞有目的地重塑核结构，并通过将从动态重塑的三维细胞外基质接收的生物物理信号传递到核来调节血管发生。

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.