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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：
9070084
负责人：
David R Sherwood
金额：
$ 53.72万
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/9070084
关键词：
Accounting Address Area Arthritis Asthma Basement membrane Behavior Biological Process Caenorhabditis elegans Cancer Patient Cells Cellular Structures Cessation of life Clinical Trials Complex Development Disease Disseminated Malignant Neoplasm Extracellular Matrix Genetic Genomic approach Health Human Immune Immunologic Surveillance In Vitro Infection Inhibition of Matrix Metalloproteinases Pathway Injury Invaded Laminin Lead 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 Genes Therapeutic Tissues Transcriptional Regulation 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.