Project 3 ADM

项目3 ADM

• 批准号: 10762126
• 负责人: THOMAS D. SCHMITTGEN
• 金额: $ 11.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762126
• 关键词: 3-Dimensional; ATAC-seq; Acinar Cell; Acinus organ component; Address; African American; African American population; Black Populations; Black race; California; Cancer cell line; Caring; Cell Line; Cell Reprogramming; Cells; Chronic; Coculture Techniques; Collagen; Conditioned Culture Media; Data; Development; Disease; Disparity; Duct (organ) structure; Ductal Epithelial Cell; Early Diagnosis; Early treatment; Education; Event; Experimental Models; Extracellular Matrix; Fibronectins; Florida; Funding; Gender; Gene Expression; Genes; Goals; Heterogeneity; Hispanic; Hispanic Populations; Histone Deacetylase Inhibitor; Human; Immune; Immunofluorescence Immunologic; In Situ; Incidence; Individual; Inflammation; Inflammatory; Institution; Latino; Latino Population; Lesion; Link; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic stress; Metaplasia; Methods; Microscopic; Molecular; Normal Range; Outcome; Oxidative Stress; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Penetration; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Pilot Projects; Process; Prognosis; Publishing; Race; Role; Sampling; Stains; Stromal Cells; System; Tissues; Trichostatin A; anticancer research; biophysical properties; biophysical techniques; cancer health disparity; chronic pancreatitis; combat; comorbidity; effective therapy; health equity; improved; inhibitor; irritation; mortality; mouse model; novel; pancreas development; pancreatic ductal adenocarcinoma model; pancreatic metaplasia; pancreatic stellate cell; pharmacologic; prevent; racial disparity; stellate cell; therapeutic target; transcriptome sequencing; treatment response; tumor microenvironment

ABSTRACT – FULL PROJECT 3 Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancers with poor prognosis and rising incidence. To combat this deadly disease, we should direct our efforts towards preventing PDAC or halting the progression of precursor lesions to invasive disease parallel to developing novel treatments. One of the earliest known initiating events for PDAC is the process of acinar-to-ductal metaplasia (ADM). Understanding and reduction of ADM formation may reduce early PDAC development and progression. Blacks display a significantly increased incidence and mortality from PDAC compared to other races for unknown reasons. The role of race on pancreatic ADM and its contributions to the development and progression of PDAC need to be addressed. In our previous studies, we used normal pancreatic acinar tissues from Black, White and Hispanic donors to study the impact of race on acinar-to-ductal metaplasia (ADM) and found that Blacks undergo ADM to a greater extent than Whites or Hispanics. In this competitive renewal, we will expand on and extend our previous study by including diseased tissues from CP and PDAC from White, Black, and Hispanic donors since accumulating evidence suggest that chronic pancreatitis (CP) is a major precursor to the development of PDAC. We will investigate the impact of race on the cellular and molecular events regulating the interplay between ADM and the microenvironment. Guided by our published and unpublished results, we hypothesize that the racial disparities seen in PDAC are related to differences in how the pancreas microenvironment develops during ADM, which means that ADM and its surrounding microenvironment can be used as a target to treat PDAC. We propose the following specific aims to address this hypothesis: Aim 1: The impact of race on ADM from the healthy pancreas, CP, and PDAC tissues. Aim 2: The roles of pancreatic stellate cells and macrophages in ADM and ADM reversal. Aim 3: Contributions of the race to ADM reversal and cell heterogeneity. The proposed studies will impact the field of pancreatic cancer by providing a missing link between disparities, ADM, tumor microenvironment, and potential treatments for CP and PDAC. The specific focus on the racial contributions of microenvironment remolding during pancreatic metaplasia aligns with the Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center’s overall goal to eliminate cancer health disparities among Blacks and Latinos in California, Florida, and across the U.S..

摘要 - 完整项目3 胰腺导管腺癌（PDAC）仍然是预后不良的最具破坏性的癌症之一 和上升事件。为了打击这种致命的疾病，我们应该将努力引导到防止PDAC或 停止前体病变的进展，使其与开发新疗法平行。之一 PDAC最早已知的启动事件是腺泡到导管变质的过程（ADM）。 了解和减少ADM形成可能会减少早期PDAC的发展和进展。黑人 与未知的其他种族相比，PDAC的发病率和死亡率显着提高 原因。种族对胰腺ADM的作用及其对发展和发展的贡献 PDAC需要解决。在以前的研究中，我们使用了黑色的正常胰腺腺泡组织 怀特和西班牙裔捐助者研究种族对腺泡到导管变质的影响（ADM），发现这一点 黑人比白人或西班牙裔更大程度地接受ADM。在这种竞争性的续约中，我们将扩展 通过包括白色，黑色和 西班牙裔捐助者自从积累证据以来，表明慢性胰腺炎（CP）是统治的主要先驱 PDAC的开发。我们将研究种族对调节细胞和分子事件的影响 ADM和微环境之间的相互作用。在我们发表和未发表的结果的指导下，我们 假设PDAC中看到的种族分布与胰腺的差异有关 ADM期间的微环境发展，这意味着ADM及其周围的微环境可以是 用作治疗PDAC的目标。我们提出以下具体目的以解决这一假设：目标1： AIM 2：来自健康胰腺，CP和PDAC组织的胰腺作用。目标2：胰腺的作用 ADM和ADM逆转的星状细胞和巨噬细胞。目标3：竞赛的贡献 和细胞异质性。拟议的研究将通过提供缺失来影响胰腺癌领域 分布，ADM，肿瘤微环境以及CP和PDAC的潜在处理之间的联系。 在胰腺变质时，对微环境的种族贡献的具体关注 随着佛罗里达 - 加利福尼亚癌症研究，教育与参与（CARE2）健康权益中心的 在加利福尼亚，佛罗里达州以及整个黑人和拉丁美洲人之间消除癌症健康分布的总体目标 美国..