Regulation of Endometriotic Lesion Development by NOTCH1

NOTCH1对子宫内膜异位病变发展的调控

• 批准号: 10379364
• 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
• 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/10379364
• 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; Human; Implant; In Vitro; Infertility; Inflammation; Inflammatory; Interleukin-6; Knowledge; Label; Lesion; Malignant Neoplasms; 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; 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; nanoparticle; notch protein; novel; novel therapeutic intervention; overexpression; prevent; promoter; receptor; reproductive; targeted delivery; targeted treatment; therapeutic target; transcription factor

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.

项目摘要 子宫内膜异位症是一种慢性、雌激素依赖性妇科疾病， 生育年龄导致盆腔疼痛和不孕。它的特点是存在子宫内膜组织 子宫外，主要是盆腔腹膜。增生性病变或植入物的活动，以及 随后粘连的发展，是疾病症状的可能原因。病变发展 在子宫内膜异位症患者中进行研究是困难的，因为在诊断上有很大的延迟。过去20 多年来，我们已经开发了狒狒作为一个适当的模型，以更好地研究建立和 增生性病变的进展。了解规范发展的机制， 疾病开始时异位病变的进展将为靶向治疗带来新的机会 以预防和/或治疗子宫内膜异位症。跨膜受体的Notch家族（NOTCH 1 -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 假设存在于炎症性腹膜环境中的IL-6诱导了 E蛋白转录因子E2 A和HEB，其反过来通过直接调节NOTCH 1表达， 与NOTCH 1启动子结合。NOTCH 1的诱导通过以下途径促进了肿瘤病变的发展： 控制细胞增殖、侵袭和EMT。在这项提案中，我们将利用我们的创新工程小鼠 模型，建立的狒狒子宫内膜异位症模型与良好表征的人体组织一起， 了解NOTCH 1是如何被诱导的，以及NOTCH 1的诱导和上调如何有助于 出现增生性病变。具体目标1将集中于IL-6在肿瘤中的分子机制， 在子宫内膜异位症的背景下，调节E蛋白转录因子（E2 A和HEB）的表达，以诱导 在体外和体内研究NOTCH 1，并确定NOTCH 1激活信号传导的分子机制 促进肿瘤病变发展的途径。具体目标2将侧重于功能研究 使用3D和类器官细胞培养模型和我们独特的荧光标记的NOTCH 1功能增益， 功能丧失小鼠模型，以剖析分子机制和病理后果， 肿瘤组织中NOTCH 1表达增加调节细胞增殖并诱导EMT增强， 移民和入侵。具体目标3将使用两个工程小鼠模型和狒狒子宫内膜异位症 用于显性失活的Mastermind样（DN-MAML）肽（SAHM 1）的靶向递送的模型， 荧光标记的纳米颗粒抑制NOTCH 1信号传导作为一种新的治疗方法，以抑制 与疾病相关的病理过程。这些研究的结果将提高我们的 了解的病因学和病理生理学的病变发展和阐明新的 这些途径将转化为确定新的非激素治疗方法， 子宫内膜异位症