Regulation of Endometriotic Lesion Development by NOTCH1

NOTCH1对子宫内膜异位病变发展的调控

基本信息

批准号：
10605178
负责人：
Asgerally T. Fazleabas
金额：
$ 55.82万
依托单位：
MICHIGAN STATE UNIVERSITY
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 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605178
关键词：
3-Dimensional Adhesions Affect Affinity Age Animal Model Binding Biology Cell Communication Cell Culture Techniques Cell Proliferation Cell Survival Cells Chronic Clinical Coupled Development Diagnosis Disease Disease Progression Dominant-Negative Mutation Endometrial Engineering Environment Ephrin B Receptor Estrogens Etiology Event Family Fluorescence Functional disorder Gynecologic Human Implant In Vitro Infertility Inflammation Inflammatory Interleukin-6 Invaded Knowledge Lesion Malignant Neoplasms Membrane Modeling Molecular NOTCH1 gene Notch Signaling Pathway Onset of illness Organoids Outcome Study Papio Pathologic Pathologic Processes Pathway interactions Pelvic Pain Pelvis Peptides Peritoneal Peritoneum Phosphorylation Proliferating Proteins Regulation Signal Pathway Signal Transduction Symptoms TCF3 gene Therapeutic Tissues Translating Up-Regulation Uterus Variant Woman angiogenesis cytokine endometriosis extracellular gain of function gene function human tissue immune function immunoregulation in vivo innovation loss of function migration mouse model nanolabel nanoparticle notch protein novel novel therapeutic intervention overexpression p38 Mitogen Activated Protein Kinase prevent promoter receptor reproductive targeted delivery targeted treatment therapeutic target transcription factor

项目摘要

Project Summary Endometriosis is a chronic, estrogen-dependent gynecological disorder affecting 10-15% of women of reproductive age resulting in pelvic pain and infertility. It is characterized by the presence of endometrial tissue outside the uterus, predominantly in the pelvic peritoneum. The activity of endometriotic lesions or implants, and the development of subsequent adhesions, is the likely causes of the disease symptoms. Lesion development is difficult to study in women with endometriosis because of the significant delays in diagnosis. In the past 20 years we have developed the baboon as an appropriate model to better examine the establishment and progression of endometriotic lesions. Understanding the mechanisms that regulate the development and progression of ectopic lesions at the onset of the disease will result in new opportunities for targeted therapies to prevent and/or treat endometriosis. The Notch family of transmembrane receptors (NOTCH1-4) transduces extracellular signals responsible for cell survival, cell-to-cell communication, and differentiation. Our Central Hypothesis is that IL-6, which is present in the inflammatory peritoneal environment induces the expression of the E-protein transcription factors E2A and HEB, which in turn upregulates NOTCH1 expression by directly binding to the NOTCH1 promoter. The induction of NOTCH1 promotes endometriotic lesion development by controlling cell proliferation, invasion and EMT. In this proposal we will utilize our innovative engineered mouse models, the established baboon endometriosis model together with well characterized human tissues to understand how NOTCH1 is induced and how the induction and upregulation of NOTCH1 contributes to endometriotic lesion development. Specific Aim 1 will focus on the molecular mechanisms by which IL-6, in the context of endometriosis, regulates the expression of E-protein transcription factors (E2A and HEB) to induce NOTCH1 in vitro and in vivo and determine the molecular mechanisms by which NOTCH1 activates signaling pathways that contribute to endometriotic lesion development. Specific Aim 2 will focus on functional studies using 3-D and organoid cell culture models and our unique fluorescence-tagged NOTCH1 gain of function and loss of function mouse models to dissect the molecular mechanisms and pathological consequences by which increased NOTCH1 expression in endometriotic tissues regulates cell proliferation and induces EMT to enhance migration and invasion. Specific Aim 3 will use both engineered mouse models and the baboon endometriosis model for targeted delivery of a dominant negative Mastermind-like (DN-MAML) peptide (SAHM1) using fluorescently labeled nanoparticles to inhibit NOTCH1 signaling as a novel therapeutic approach to inhibit the pathologic processes associated with the disease. The outcomes of these studies will enhance our understanding of the etiology and pathophysiology of endometriotic lesion development and elucidate novel pathways which will translate into identifying novel non-hormonal therapeutic approaches for treating endometriosis.

项目概要子宫内膜异位症是一种慢性、雌激素依赖性妇科疾病，影响 10-15% 的女性生育年龄导致骨盆疼痛和不孕。其特征是存在子宫内膜组织子宫外，主要是盆腔腹膜。子宫内膜异位病变或植入物的活动，以及随后粘连的发展，是该疾病症状的可能原因。病变发展由于诊断严重延迟，因此很难在患有子宫内膜异位症的女性中进行研究。在过去的20 多年来，我们开发了狒狒作为适当的模型，以更好地检查建立和子宫内膜异位病变的进展。了解调节发育和发育的机制疾病发作时异位病变的进展将为靶向治疗带来新的机会预防和/或治疗子宫内膜异位症。 Notch 跨膜受体家族 (NOTCH1-4) 转导负责细胞存活、细胞间通讯和分化的细胞外信号。我们的中央假设炎症腹膜环境中存在的 IL-6 诱导 E 蛋白转录因子 E2A 和 HEB，进而通过直接上调 NOTCH1 表达与 NOTCH1 启动子结合。 NOTCH1的诱导通过以下方式促进子宫内膜异位病变的发展控制细胞增殖、侵袭和 EMT。在本提案中，我们将利用我们的创新工程鼠标模型，建立的狒狒子宫内膜异位症模型与特征明确的人体组织一起了解 NOTCH1 是如何被诱导的以及 NOTCH1 的诱导和上调如何有助于子宫内膜异位病变的发展。具体目标 1 将重点关注 IL-6 在子宫内膜异位症的背景下，调节 E 蛋白转录因子（E2A 和 HEB）的表达以诱导 NOTCH1 体外和体内实验并确定 NOTCH1 激活信号传导的分子机制有助于子宫内膜异位病变发展的途径。具体目标 2 将侧重于功能研究使用 3-D 和类器官细胞培养模型以及我们独特的荧光标记 NOTCH1 功能增益和功能丧失小鼠模型来剖析分子机制和病理后果子宫内膜异位组织中NOTCH1表达增加调节细胞增殖并诱导EMT增强迁徙和入侵。 Specific Aim 3 将使用工程小鼠模型和狒狒子宫内膜异位症模型使用显性失活 Mastermind 样 (DN-MAML) 肽 (SAHM1) 进行靶向递送的模型荧光标记纳米颗粒抑制 NOTCH1 信号传导作为抑制 NOTCH1 信号传导的新型治疗方法与疾病相关的病理过程。这些研究的结果将增强我们的了解子宫内膜异位病变发展的病因学和病理生理学并阐明新的途径将转化为识别新的非激素治疗方法子宫内膜异位症。