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.

项目总结