Regulation of hormone production by matrix proteins

基质蛋白调节激素产生

基本信息

批准号：
8628083
负责人：
Rong Li
金额：
$ 29.91万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628083
关键词：
Accounting Adipose tissue Adverse effects Affect Anabolism Animal Model Area Aromatase Aromatase Inhibition Atomic Force Microscopy Behavior Biochemical Biological Models Breast Cells Chromatin Clinical Coculture Techniques Data Dinoprostone Endocrine Endocrine System Diseases Enzymes Estradiol Estrogens Etiology Extracellular Matrix Extracellular Matrix Proteins Family Focal Adhesion Kinase 1 Functional disorder Gene Expression Genes Genetic Transcription Homeostasis Hormones Human In Vitro Integrins Knowledge Ligands Link Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measures Mechanics Mediating Molecular Mus Nature Nuclear Obesity Organ Pathway interactions Play Positioning Attribute Post-Translational Protein Processing Postmenopause Production Property Proteins Regulation Research Role Sampling Signal Pathway Signal Transduction Signaling Molecule Stromal Cells System Testing Tissues Transcription Factor AP-1 Uterine Fibroids Woman Work anticancer research biophysical tools cancer risk endometriosis hormone metabolism hormone regulation in vivo in vivo Model integrin-linked kinase malignant breast neoplasm malignant endocrine gland neoplasm member neoplastic cell new therapeutic target novel overexpression paracrine prognostic promoter receptor research study therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Our overall objective is to elucidate how extracellular matrix (ECM) stimulates hormone production. Several estrogen-dependent pathological conditions including breast cancer, uterine fibroids, and endometriosis are associated with local overexpression of aromatase, a key enzyme in estrogen biosynthesis and important therapeutic target for postmenopausal ER+ breast cancer. In addition, excessive aromatase expression in adipose tissue at least partially accounts for obesity-associated breast cancer risk among postmenopausal women. While altered matrix homeostasis is associated with these aromatase- overexpressing tissues, little is known as to whether it can directly impact local steroidogenic gene expression and estrogen biosynthesis. A paucity of knowledge in this area is partly due to the lack of proper model systems that can recapitulate the mechanical properties of a cell's microenvironment. We hypothesize that ECM is a previously unappreciated critical determinant for local aromatase overexpression and estrogen production. In support of this hypothesis, our preliminary data indicate that matrix alone can significantly stimulate aromatase transcription in breast stromal cells (BSCs) via distinct signaling pathways. We have a repertoire of molecular and biophysical tools, in vitro and in vivo model systems, and cross-disciplinary expertise to further test the hypothesis. Specifically, we will first determine how ligand-receptor interactions rigidity, and three-dimensionality of a matrix affect aromatase expression; and how the matrix signals are sensed by cellular mechanosensory apparatus (Aim 1). We will then determine how the intracellular signaling cascades relay the matrix signals to the transcription machinery at the aromatase gene (Aim 2). Lastly, we will use in vitro co-culture systems, humanized animal models, and clinical samples to examine the functional consequences of matrix-induced stromal aromatase expression (Aim 3). The link between matrix homeostasis and hormone metabolism is a vastly under-explored topic. When successfully executed, the proposed work promises to fill a major gap of knowledge in this field. Findings from the study may also provide novel prognostic tools and markers, as well as new therapeutic targets for reducing local estrogen production, thus overcoming the side effects often associated with systemic inhibition of aromatase. In a broader sense, the conceptual and technical advances achieved in the current proposal may offer guidance to research on endocrine/paracrine dysfunction in a variety of tissues and organs.

描述（由申请人提供）：我们的总体目标是阐明细胞外基质（ECM）如何刺激激素的产生。几种雌激素依赖性病理状况，包括乳腺癌，子宫肌瘤和子宫内膜异位症与芳香酶的局部过表达有关，芳香酶的局部过表达是雌激素生物合成中的关键酶，以及绝经后ER+乳腺癌的重要治疗靶标。此外，绝经后妇女中与肥胖相关的乳腺癌风险至少部分解释了脂肪组织中的芳香化酶表达过多。虽然改变的基质稳态与这些芳香酶过表达的组织相关，但鲜为人知它是否可以直接影响局部类固醇基因表达和雌激素生物合成。在这一领域的知识很少，部分原因是缺乏适当的模型系统，这些模型系统可以概括细胞的微环境的机械性能。我们假设ECM是局部芳香酶过表达和雌激素产生的先前未批准的关键决定因素。为了支持这一假设，我们的初步数据表明，单独的基质可以通过不同的信号通路显着刺激乳腺基质细胞（BSC）中的芳香化酶转录。我们拥有分子和生物物理工具，体外和体内模型系统的曲目，以及跨学科的专业知识，以进一步检验该假设。具体而言，我们将首先确定配体 - 受体相互作用如何刚度和基质的三维影响芳香化酶的表达。以及如何通过细胞机械感应设备感测矩阵信号（AIM 1）。然后，我们将确定细胞内信号传导如何将基质信号传递到转录机制芳香酶基因（AIM 2）。最后，我们将使用体外共培养系统，人源化的动物模型和临床样本来检查基质诱导的基质芳香酶表达的功能后果（AIM 3）。基质稳态与激素代谢之间的联系是一个爆发较大的话题。成功执行后，拟议的工作有望填补该领域的主要知识差距。该研究的结果还可以提供新颖的预后工具和标记物，以及减少局部雌激素产生的新治疗靶标，从而克服了通常与全身性抑制芳香酶有关的副作用。从广义上讲，当前提案中实现的概念和技术进步可能会为各种组织和器官中内分泌/旁分泌功能障碍的研究提供指导。