Profilin biology in breast cancer

乳腺癌中的Profilin生物学

基本信息

批准号：
10377334
负责人：
PARTHA ROY
金额：
$ 34.57万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377334
关键词：
1-Phosphatidylinositol 3-Kinase Actin-Binding Protein Actins Adenocarcinoma Animals Behavior Binding Biochemical Biological Assay Biology Biosensor Breast Cancer Cell Breast cancer metastasis Cell membrane Cells Cessation of life Clinical Cytoskeleton Cytosol Data Diagnosis Diffusion Down-Regulation Extracellular Matrix Family Generations Goals Human Hydrolysis INPPL1 gene Image Immunofluorescence Immunologic Immunohistochemistry In Vitro Invaded Knowledge Lead Link Lipids Malignant - descriptor Malignant Neoplasms Mediating Membrane Metastatic breast cancer Modeling Molecular Neoplasm Metastasis PTEN gene Pathway interactions Phenotype Phosphatidylinositols Phospholipase C Phosphoric Monoester Hydrolases Physiological Primary Neoplasm Proline Protein Dephosphorylation Protein Dynamics Proteins Proto-Oncogene Proteins c-akt Regulation Resolution Role Sampling Signal Pathway Signal Transduction Study models Testing Time Tumor Cell Biology Tumor Cell Invasion United States Up-Regulation Woman Zebrafish antagonist arm base cancer cell cell motility gain of function genetic regulatory protein in vivo insight intravital imaging live cell imaging malignant breast neoplasm migration mouse model neoplastic cell novel phosphoinositide-3,4,5-triphosphate phosphoinositide-3,4-bisphosphate profilin recruit residence single molecule tumor progression vasodilator-stimulated phosphoprotein

项目摘要

Breast cancer the most frequently diagnosed non-skin cancer in women, ranks second among cancer deaths in women in the United States. The vast majority of these deaths are due to metastasis. Dysregulated expression and/or activity of actin-regulatory proteins contribute to the motile phenotype that enables metastatic dissemination of breast cancer cells. The goal of this study is to gain fundamental mechanistic insights into how profilin1, a major regulator of actin cytoskeleton, influences cell signaling at the membrane-cytosol interface that are important for early steps of breast cancer metastasis. We propose two specific aims in the project. In Aim 1, we will elucidate how profilin1’s binding to cell membrane alters membrane phosphoinositide dynamics in cells. In aim 2, we will further establish a causal connection between profilin1- dependent modulation of membrane phosphoinositide signaling and phosphoinositide-directed pro-migratory signaling axis in regulating metastatic dissemination of breast cancer cells from the primary tumor. These studies will utilize a comprehensive experimental approach combining high- resolution live cell imaging of lipid biosensors, imaging of membrane diffusion dynamics of proteins at the single molecule level, intravital imaging of cancer cell dissemination and clinical sample analyses. A succesful completion of this study will provide novel mechanisms for breast cancer dissemination.

乳腺癌是女性最常见的非皮肤癌，在美国妇女的癌症死亡。这些死亡的绝大多数是由于转移。肌动蛋白调节蛋白的表达和/或活性失调有助于能够使乳腺癌细胞转移性传播的运动表型。目标的目标研究是为了获得有关肌动蛋白的主要调节剂Profilin1如何获得基本的机理见解细胞骨架，影响膜 - 胞质剂界面处的细胞信号传导，这对于对乳腺癌转移的早期步骤。我们在项目中提出了两个具体目标。在AIM 1中，我们将阐明Profilin1与细胞膜的结合如何改变膜磷酸肌醇细胞中的动力学。在AIM 2中，我们将进一步建立Profilin1-之间的因果关系膜磷酸肌醇信号传导和磷酸肌醇指导的依赖调制控制乳腺癌细胞从原发性肿瘤。这些研究将采用一种全面的实验方法，结合了高度分辨率的脂质生物传感器的活细胞成像，膜扩散动力学成像单分子水平的蛋白质，癌细胞传播和临床的浸润成像样本分析。这项研究的成功完成将为乳房提供新的机制癌症传播。