Racial contributions of microenvironment remolding during pancreatic metaplasia

胰化生过程中微环境重塑的种族贡献

• 批准号: 10762214
• 负责人: Jamel Ali
• 金额: $ 8万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762214
• 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 ADM 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 previously funded CaRE2 Pilot Project, 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 proposed Full Project as part of the CaRE2 renewal, we will expand on and extend our previous pilot project 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 influence of race on ADM of healthy pancreas, CP, and PDAC-associated acinar 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 Black and Latino individuals in California, Florida, and across the U.S.

摘要-完整项目3 ADM 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。理解 减少ADM的形成可减少PDAC的早期发生和进展。黑人表现出 与其他种族相比，PDAC的发病率和死亡率显著增加，原因不明。的 种族对胰腺ADM的作用及其对PDAC发生和进展的贡献需要进一步研究。 处理。在我们之前资助的CaRE 2试点项目中，我们使用了来自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。在这个拟议的完整项目中， CaRE 2更新，我们将扩大和扩展我们以前的试点项目，包括从CP患病组织 以及来自白色、黑人和西班牙裔供体的PDAC，因为越来越多的证据表明， 胰腺炎（CP）是PDAC发展的主要前兆。我们将调查种族对 调节ADM和微环境之间相互作用的细胞和分子事件。引导我们的 根据已发表和未发表的结果，我们假设在PDAC中看到的种族差异与以下因素有关： 胰腺微环境在ADM过程中如何发展的差异，这意味着ADM及其 周围微环境可以作为治疗PDAC的靶点。我们提出以下具体目标 目的1：种族对健康胰腺、CP和PDAC相关ADM的影响 腺泡组织目的2：胰腺星状细胞和巨噬细胞在ADM和ADM逆转中的作用 种族对ADM逆转和细胞异质性的贡献。拟议的研究将影响以下领域： 胰腺癌通过提供差异，ADM，肿瘤微环境和潜在的 CP和PDAC的治疗。特别关注种族对微环境重塑的贡献 在胰腺化生期间与佛罗里达-加利福尼亚癌症研究，教育和参与保持一致 （CARE 2）健康公平中心的总体目标是消除黑人和拉丁美洲人之间的癌症健康差异 加州、佛罗里达和美国各地的个人。