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（pancreatic ductal adenocarcinoma，PDAC）是一种预后差的恶性肿瘤 发病率不断上升为了对抗这种致命的疾病，我们应该努力预防PDAC， 阻止前驱病变进展为侵袭性疾病，同时开发新的治疗方法。之一 已知最早的PDAC起始事件是腺泡-导管化生（ADM）过程。 了解和减少ADM的形成可能会减少早期PDAC的发展和进展。黑人 与其他种族相比，PDAC的发病率和死亡率显着增加， 原因种族在胰腺ADM中的作用及其在胰腺癌发生发展中的作用 PDAC需要解决。在我们以前的研究中，我们使用来自Black的正常胰腺腺泡组织， 白色和西班牙裔供体研究种族对腺泡-导管化生（ADM）的影响，发现 黑人比白人或西班牙裔人更容易接受ADM。在这次竞争性的更新中，我们将扩大 通过包括来自白色、黑色和白色的CP和PDAC的病变组织， 西班牙裔捐赠者，因为越来越多的证据表明，慢性胰腺炎（CP）是一个主要的前兆， 发展PDAC。我们将研究种族对细胞和分子事件的影响， ADM和微环境之间的相互作用。根据我们已发表和未发表的结果，我们 我假设在PDAC中看到的种族差异与胰腺 微环境在ADM过程中发展，这意味着ADM及其周围的微环境可以 用作治疗PDAC的靶点。我们提出以下具体目标来解决这一假设：目标1： 种族对来自健康胰腺、CP和PDAC组织的ADM的影响。目的2：胰腺的作用 星形细胞和巨噬细胞在ADM和ADM逆转中的作用。目标3：种族对ADM逆转的贡献 和细胞异质性。拟议的研究将通过提供一个缺失的 差异、ADM、肿瘤微环境与CP和PDAC的潜在治疗之间的联系。的 特别关注胰腺化生期间微环境重塑的种族贡献， 佛罗里达-加利福尼亚癌症研究，教育和参与（CaRE2）健康公平中心 总体目标是消除加州、佛罗里达和其他地区黑人和拉丁美洲人之间的癌症健康差异。 美国。