Understanding how cells invade through basement membrane in vivo

了解体内细胞如何侵入基底膜

基本信息

批准号：
9279198
负责人：
David R Sherwood
金额：
$ 58.57万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279198
关键词：
Address Area Arthritis Asthma Basement membrane Behavior Biological Process Caenorhabditis elegans Cancer Patient Cell model Cell physiology Cells Cellular Structures Cessation of life Clinical Trials Complex Development Disease Disseminated Malignant Neoplasm Extracellular Matrix Genetic Genetic Transcription Genomic approach Health Human Immune Immunologic Surveillance In Vitro Infection Inhibition of Matrix Metalloproteinases Pathway Injury Invaded Laminin Malignant Neoplasms Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Membrane Mission Mitochondria Molecular Multiple Sclerosis Neoplasm Metastasis Play Pre-Eclampsia Research Role Site Specific qualifier value Structural Protein Therapeutic Tissues Transcriptional Regulation United States National Institutes of Health Vertebrates Visual Work cell motility crosslink functional genomics human disease in vivo in vivo Model novel therapeutic intervention overexpression programs public health relevance trafficking tumor progression

项目摘要

DESCRIPTION (provided by applicant): Basement membrane is a dense, highly cross-linked form of extracellular matrix that surrounds most tissues. During development and immune surveillance, specialized cells acquire the ability to breach basement membrane to disperse and traffic to sites of infection and injury. The cell invasion program is misregulated during many diseases, including asthma, arthritis, multiple sclerosis, and pre-eclampsia. The inappropriate acquisition of invasive behavior also underlies the spread of cancer, which accounts for 90% of all cancer- related deaths. Understanding how cells invade through basement membrane is thus of great importance to human health. Cell invasion involves dynamic interactions between the invading cell, the tissue being invaded, and the basement membrane separating them. Owing to an inability to recapitulate these complex interactions in vitro, and the challenge of experimentally examining invasion in vivo in vertebrates, the mechanisms underlying cell invasive behavior remain poorly understood. Anchor cell invasion in C. elegans is an experimentally accessible in vivo model of cell invasion that uniquely combines subcellular visual analysis of cell-basement membrane interactions with powerful forward genetic and functional genomic approaches. Using these strengths, our work will characterize a newly identified cellular structure-the invasive protrusion, a specialized membrane domain that both degrades and physically displaces basement membrane during invasion. We will also determine how secretion of the basement membrane structural protein laminin by the invading anchor cell facilitates invasion. Most metastatic tumors overexpress laminin, and we expect this work to have wide relevance to understanding cancer progression. Our studies have also unexpectedly revealed that the anchor cell can invade basement in the absence of matrix metalloproteinases (MMPs) by physically displacing the basement membrane. This finding might explain why inhibition of MMPs in clinical trials of metastatic cancer patients failed. Our work will determine how the anchor cell alters its invasion mode and investigate an increased requirement for mitochondrial generated ATP to compensate for the loss of MMPs. These findings will begin a new research area in energy requirements during cell invasion and inform better approaches to target invasion with MMP inhibitors. Finally, our work will characterize a nascent transcriptional regulatory network that specifies invasion, thus addressing the crucial question of how cells are programmed to be invasive. These integrative studies spanning specialized cellular invasive machinery, basement membrane remodeling and transcriptional regulation are relevant to NIH's mission as they will lead to a deep understanding of the fundamental biological process of cell invasive behavior, thus allowing the development of better therapeutic strategies to limit invasion in human diseases such as cancer.

描述（由适用提供）：地下膜是大多数组织周围的细胞外基质的密集，高度交联的形式。在发育和免疫监视过程中，专门的细胞获得了违反地下膜以分散和交通的能力，并流量到感染和受伤部位。在许多疾病中，包括哮喘，关节炎，多发性硬化症和胚胎前的疾病中，细胞侵袭程序被误导。对侵入性行为的不当收购也构成了癌症的传播，占所有与癌症相关的死亡的90％。因此，了解细胞如何通过基底膜侵袭对人类健康至关重要。细胞侵袭涉及入侵细胞，组织入侵的动态相互作用以及将其分开的基底膜。由于无法在体外概括这些复杂的相互作用以及实验检查体内脊椎动物的侵袭的挑战，因此细胞侵入性行为的基础机制仍然很众所周知。秀丽隐杆线虫中的锚细胞侵袭是一种实验可访问的细胞浸润模型，它独特地结合了细胞膜膜相互作用的亚细胞视觉分析与强大的正向遗传和功能基因组方法。利用这些优势，我们的工作将表征新近鉴定的细胞结构 - 浸润蛋白，这是一种专门的膜结构域，在侵袭过程中既有降解和物理置换基底膜。我们还将确定如何通过入侵的锚固细胞女主人入侵对基底膜结构蛋白层粘连蛋白的分泌。大多数转移性肿瘤过表达层粘连蛋白，我们希望这项工作具有广泛的相关性，以了解癌症的进展。我们的研究还意外地表明，在没有基质金属蛋白酶（MMP）的情况下，锚固细胞可以通过物理位移基底膜入侵地下室。这一发现可能解释了为什么在转移性癌症患者的临床试验中抑制MMP的原因失败了。我们的工作将决定锚固细胞如何改变其侵袭模式并研究对线粒体产生的ATP的需求增加，以补偿MMP的损失。这些发现将在细胞侵袭过程中开始在能量需求方面的新研究领域，并为使用MMP抑制剂提供更好的靶向入侵方法。最后，我们的工作将表征一个新生的转录调节网络，该网络指定了入侵，从而解决了如何编程细胞为侵入性的关键问题。这些综合研究涵盖了专业的细胞侵入性机械，基底膜重塑和转录调控与NIH的任务有关，因为它们将深入了解细胞侵入性行为的基本生物学过程，从而允许更好地治疗策略来限制诸如癌症之类的人类疾病的入侵。