Full Project 3

摘要-完整项目3 ADM 摘要胰腺导管腺癌(PDAC)是最具破坏性的癌症之一，预后差。 以及不断上升的发病率。为了抗击这种致命的疾病，我们应该将我们的努力指向预防PDAC或 在开发新治疗方法的同时，阻止前驱病变向侵袭性疾病的进展。其中之一 已知的最早的PDAC始发事件是腺泡-导管化生(ADM)过程。理解 减少ADM的形成可能会减缓PDAC的早期发生和进展。黑色显示为 与其他种族相比，由于未知原因，PDAC的发病率和死亡率显著增加。这个 RACE在胰腺ADM中的作用及其在PDAC发生发展中的作用 地址。在我们之前资助的Care2试点项目中，我们使用了Black的正常胰腺腺泡组织， 白人和西班牙裔捐赠者研究种族对腺泡至导管化生(ADM)的影响，并发现 黑人患ADM的程度比白人或西班牙裔更严重。在这个拟议的完整项目中，作为 Care2更新，我们将扩大和延长我们之前的试点项目，包括CP的病变组织 和来自白人、黑人和西班牙裔捐赠者的PDAC，因为越来越多的证据表明慢性 胰腺炎(CP)是PDAC发生的主要先兆。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。由我们的指导 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 在ADM过程中胰腺微环境如何发展的差异，这意味着ADM及其 周围微环境可作为治疗PDAC的靶点。我们提出了以下具体目标 为了解决这一假设：目标1：种族对健康胰腺、CP和PDAC相关患者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 小种对ADM逆转和细胞异质性的贡献。拟议的研究将影响 胰腺癌通过提供差异、ADM、肿瘤微环境和潜能之间缺失的联系 CP和PDAC的治疗。特别关注微环境重塑的种族贡献 在胰腺化生期间与佛罗里达-加州癌症研究、教育和参与相一致 (Care2)健康公平中心的总体目标是消除黑人和拉丁裔之间的癌症健康差距 加利福尼亚州、佛罗里达州和美国各地的个人。

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 Guided by our published and unpublished results, we hypothesize that the racial disparities seen in PDAC are related to differences in how the pancreas microenvironment develops during ADM, which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.