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中文摘要
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描述(由申请人提供):人胃腺癌在幽门螺杆菌诱导的泌酸萎缩和慢性粘液细胞化生的背景下演变。我们最近的谱系作图研究表明,小鼠胃底化生不是由位于腺体上颈区的专职祖细胞引起的,而是由成熟主细胞转分化为表达痉挛性多肽的化生(SPEM)。这些研究已经导致了一个显着的范式转变的概念,胃肿瘤的起源,这表明,肿瘤前谱系不产生专业居民粘膜祖细胞群体,而是从成熟的酶原细胞谱系的转分化。此外,现在多项研究表明,SPEM在炎症的影响下,可以发展增殖增加和增殖基因表达水平增加,并且在人类中引起杯状细胞肠化生。我们最近的研究表明,巨噬细胞负责促进增殖性SPEM进展,但负责SPEM向增殖和发育不良进展的精确介质仍然未知。因此,我们推测,离散的内在粘膜和巨噬细胞衍生因子调节不仅演变,但也进展的SPEM更多的增殖,癌前化生。为了解决这一假设,我们将追求两个具体的目标:首先,我们将研究巨噬细胞在化生的演变和进展中的作用。第二,我们将评估Ras激活在从转分化主细胞进化出SPEM中的作用,以及在由主细胞中激活的K-Ras的诱导表达驱动的化生的新模型中SPEM谱系的进一步分化。虽然我们以前的研究集中在通过主细胞转分化产生化生的新途径的建立上,但本研究现在集中在通过主细胞转分化产生化生的新途径上。 可能驱动化生到癌前病变的机制。
英文摘要
DESCRIPTION (provided by applicant): Adenocarcinoma in the human stomach evolves in the setting of Helicobacter pylori- induced oxyntic atrophy and chronic mucous cell metaplasia. Our recent lineage mapping studies have demonstrated that metaplasia in the gastric fundus in mice does not arise from the professional progenitor cells located in the upper neck region of the glands, but rather develops from transdifferentiation of mature chief cells into Spasmolytic Polypeptide Expressing Metaplasia, or SPEM. These studies have led to a significant paradigm shift in the concepts for the origin of gastric neoplasia, suggesting that pre-neoplastic lineages do not arise from professional resident mucosal progenitor cell populations, but rather develop from transdifferentiation of mature zymogenic cell lineages. Furthermore, multiple studies now indicate that SPEM, under the influence of inflammation, can develop both increased proliferation and increasing levels of intestinalizing gene expression, and in humans gives rise to goblet cell intestinal metaplasia. Our recent investigations have demonstrated that macrophages are responsible for the promotion of proliferative SPEM progression, but the precise mediators that are responsible for the progression of SPEM towards intestinalization and dysplasia remain unknown. We therefore hypothesize that discrete intrinsic mucosal and macrophage-derived factors regulate not only the evolution, but also the progression of SPEM to more proliferative, preneoplastic metaplasia. To address this hypothesis, we will pursue two specific aims: First, we will examine the role of macrophages in the evolution and progression of metaplasia. Second, we will evaluate the role of Ras activation in evolution of SPEM from transdifferentiating chief cells and the further intestinalization of SPEM lineages in a novel model of metaplasia driven by inducible expression of activated K-Ras in chief cells. While our previous investigations have focused on the establishment of a novel pathway for generation of metaplasia through transdifferentiation of chief cells, the present investigations now focus on the mechanisms that might drive metaplasias to preneoplasia.
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COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository
COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository
COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository
COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository
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