Molecular mechanisms of gap junction promotion of lesion formation in Endometriosis

间隙连接促进子宫内膜异位症病变形成的分子机制

基本信息

批准号：
10772708
负责人：
BRUCE J NICHOLSON
金额：
$ 21.7万
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：
2023
资助国家：
美国
起止时间：
2023-07-28 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10772708
关键词：
3-Dimensional Address Adhesions Affect Age Area Asian Asian population Attention Biological Biological Markers Biological Testing Biology Biotechnology Black Populations Black race Categories Cell Communication Cell Separation Cells Cellular Structures Chronic Clinical Research Clinical Trials Connexins Coupling Data Data Set Development Diagnosis Diagnostic Diagnostic Trial Disease Disparity Endometrial Endometrial Stromal Cell Endometrium Epigenetic Process Epithelial Cells Ethnic Origin Ethnic Population Female Frequencies Functional disorder Future Gap Junctions Gene Expression Gene Expression Profile Genes Genetic Guidelines Gynecologic Happiness Health Health behavior Healthcare Hearing Hispanic Hispanic Populations Hospitalization Infertility Invaded Investigation Lesion Life Cycle Stages Measurement Measures Mediator Mesothelial Cell Mesothelium Methodology Modeling Molecular Not Hispanic or Latino Parents Patients Pattern Peritoneal Phenotype Physiological Population Proteins Race Reproductive Health Research Residual state Sample Size Sampling Severity of illness Site Strategic Planning Stromal Cells Testing Texas Therapeutic Intervention Woman Women&apos s Health Work accurate diagnostics analytical tool base biobank biomarker development black patient cell behavior cell type cost disease diagnosis endometriosis epithelial to mesenchymal transition ethnic difference ethnic disparity gene panel genetic regulatory protein health disparity improved intercellular communication machine learning model outreach program patient population personalized therapeutic protein expression racial disparity recruit repository reproductive response screening screening panel single cell analysis sociodemographic factors socioeconomic disparity socioeconomics stem tool treatment strategy unconscious bias

项目摘要

ABSTRACT This request for a Supplement to RO1HD109027 is in response to RFA NOT-OD-22-208 that addresses several of the priority ORWH Strategic Plan Objectives related to disparities in Women’s Health, specifically: 1.5 (Research on gynecological health, including infertility): Endometriosis is a major issue in gynecological health affecting 10% of women worldwide, of whom as many as 50% suffer problems of infertility 2.2 (Development of biomarkers for women’s health): The current work arises from our development of a much- needed non-surgical diagnostic that is being developed by Hera Biotech (co-founded by the PI and Co-I), who are sponsoring the clinical trial which will provide material for study here to assess if the diagnostic is equally effective across different ethnic groups, and if it reveals different severity of disease. 2.4 (Examination of health disparities stemming from factors such as race and ethnicity). We will expand functional tests on patient endometrial cells proposed in the parent RO1 to definitively test if there are Biological or epigenetic differences that could explain the 3-fold lower rate of diagnosis and 2 fold lower hospitalizations for endometriosis in the Hispanic (and Black) populations compared to non-Hispanic Whites. Absence of such evidence will provide the first hard data to support efforts to address the socioeconomic inequities responsible. The work proposed will utilize our expertise in single cell analysis (Co-I is Director of the Bioanalytics & Single Cell Facility) and ex-vivo functional analyses of cell interactions and invasiveness developed in the Nicholson lab under the parent RO1. We will also utilize our unique S. Texas Ob/Gyn repository of separated endometrial stromal and epithelial cells, which will be trebled in size through the on-going Hera Proof-of-Concept trial. With ~30% of samples being of Hispanic origin, this allows us to conduct the first ever in-depth comparison of gene expression patterns (Aim 1) and cellular phenotypes (Aim 2) between Hispanic and non-Hispanic white control and endometriosis patients. The scope of this short-term study will be kept manageable by focusing in Aim 1 on proteins in the “cell-interactome” – cell components involved in intercellular communication (gap junctions), contact (tight and adhesion junctions), accessory components and regulatory factors (including mediators of epithelial to mesenchymal transition). The Aim 2 functional studies will have a similar focus, concentrating on peritoneal invasiveness in a 3-D ex-vivo model using established and primary mesothelial cells, and measurements of intercellular coupling via gap junctions, as we have demonstrated this to be required for invasion. Should differences be detected, they will provide important guidelines for future personalized therapeutics. Should no differences be observed, it will provide a compelling, data-driven mandate to address the socio-economic or unconscious bias issues that contribute to ethnic disparities in endometriosis treatment.

抽象的此请求RO1HD109027的补充要求是对RFA Not-22-208的回应特别是与妇女健康方面的差异有关的优先或WH的战略计划目标，特别是： 1.5（关于妇科健康的研究，包括不育）：子宫内膜异位症是妇科的主要问题健康影响全球10％的妇女，其中多达50％的妇女遭受不育问题 2.2（妇女健康生物标志物的发展）：目前的工作是由于我们发展了很多 Hera Biotech（由PI和CO-I共同创立）正在开发的需要非手术诊断，谁正在赞助临床试验，该试验将在这里提供研究材料，以评估诊断是否平均在不同种族的群体中有效，如果揭示了不同的疾病严重程度。 2.4（检查诸如种族和种族等因素的健康差异）。我们将扩展对母体RO1中提出的患者子宫内膜细胞的功能测试，以确定测试是否存在生物学或表观遗传差异，可以解释诊断率降低3倍，而2倍的住院率降低了与非西班牙裔白人相比，西班牙裔（和黑人）种群的子宫内膜异位症。没有这样的证据将提供第一个硬数据，以支持解决负责社会经济不平等的努力。提出的工作将利用我们的专业知识在单细胞分析中（Co-I是生物分析的主管＆单细胞设施）和对细胞相互作用和侵入性的现场功能分析在尼科尔森（Nicholson）实验室在父母RO1下。我们还将利用我们独特的S. Texas ob/Gyn Spior库子宫内膜基质和上皮细胞，它们将通过持续的HERA概念验证将其大小分布审判。约有30％的样本是西班牙裔起源，这使我们能够进行第一个深入的比较基因表达模式（AIM 1）和细胞表型（AIM 2）在西班牙裔和非西班牙裔白色之间对照和子宫内膜异位症患者。这项短期研究的范围将通过关注目标1对“细胞 - 相互分泌室”中的蛋白质 - 与细胞间通信有关的细胞成分（GAP）连接），接触（紧密和粘合连接），附件组件和监管因素（包括上皮向间充质转变的介体）。 AIM 2功能研究将具有类似的重点，使用已建立的和原代的间皮细胞，专注于3-D外运动模型中的腹膜侵入性，通过间隙连接的细胞间耦合的测量，因为我们已经证明了这是必需的入侵。如果检测到差异，它们将为将来的个性化提供重要的准则疗法。如果未观察到差异，它将提供令人信服的，数据驱动的授权来解决社会经济或无意识的偏见问题导致子宫内膜异位症治疗中的种族差异。