The LIN28b-Let7 axis in intestinal epithelial biology

性状（由申请人提供）：肠上皮细胞沿隐窝-梯度绒毛沿着处于增殖、分化和凋亡的动态平衡状态。 干细胞存在于隐窝基底中，被称为隐窝基底柱状（CBC）细胞，其活跃地增殖，并且第二静止群体存在于+4位置。 这两个干细胞群体之间的相互关系是备受关注的焦点。在感染、炎症和恶性转化（腺瘤性息肉、结直肠癌）的状态下，正常的肠道内稳态被扰乱。 我们的工作已经介绍和阐明了mRNA结合蛋白在肠/结肠上皮稳态和稳态畸变中的作用，包括过度增殖、代谢改变和转化。 LIN 28 B是一种mRNA结合蛋白，在胚胎干细胞中也是关键的，转录后调节let-7 microRNA家族并导致分化抑制。反过来，Let-7 microRNA具有不同的mRNA靶点，包括我们已经详细阐述的，即Igf 2 mRNA结合蛋白-1（IMP-），一种最初被鉴定为c-Myc和Igf 2 mRNA翻译调节剂的mRNA结合蛋白。 我们已经证明LIN 28 B调节肠/结肠增殖、迁移、侵袭和生长。此外，如我们所揭示的，IMP-1显示与K-Ras的串扰并调节结肠癌细胞存活。 该提议的总体假设是LIN 28 b通过Let-7依赖性机制以及通过涉及靶向参与细胞代谢的mRNA的Let-7非依赖性机制促进肠/结肠上皮细胞增殖、生长和转化，促进生长和转化。 此外，IMP-1是LIN 28 B-Let-7介导的作用的无价执行者。 我们将通过以下相互关联的具体目标来实现这一假设：（1）阐明LIN 28 B与c-MYC在肠上皮生物学中的相互关系。（2）评价LIN 28 B在肠隐窝生物学中的Let-7依赖性和Let-7非依赖性作用。（3）研究IMP-1在肠上皮细胞中的生物学特性。总之，我们的创新研究揭示了LIN 28 B-Let-7-IMP-1轴如何调节肠上皮稳态和畸变的新见解，并开始揭示新的途径，这反过来可能具有翻译应用（诊断，预后和治疗）。

DESCRIPTION (provided by applicant): The intestinal epithelium is in a dynamic equilibrium of proliferation, differentiation and apoptosis along the crypt-villus gradien. Stem cells reside in the crypt base and are referred to as crypt base columnar (CBC) cells, which are actively proliferating, and a second, quiescent population resides in he +4 position. The interrelationship between these two populations of stem cells is the focus of much attention. Normal intestinal homeostasis is disturbed during states of infection, inflammation and malignant transformation (adenomatous polyps, colorectal cancer). Our work has introduced and elucidated the role of mRNA binding proteins in intestinal/colonic epithelial homeostasis and aberrations in homeostasis, including hyperproliferation, altered metabolism and transformation. LIN28B, a mRNA binding protein, also critical in embryonic stem cells, post- transcriptionally regulates the let-7 microRNA family and results in suppression of differentiation. In turn, Let-7 microRNAs have diverse mRNA targets, including what we have elaborated upon, namely Igf2 mRNA binding protein-1 (IMP-), an mRNA binding protein originally identified as a translational modulator of c-Myc and Igf2 mRNAs. We have demonstrated that LIN28B modulates intestinal/colonic proliferation, migration, invasion and growth. Additionally, IMP-1, as revealed by us, displays crosstalk with K-Ras and modulates colon cancer cell survival. The overall hypothesis of this proposal is that LIN28b promotes intestinal/colonic epithelial proliferation, growth and transformation through Let-7 dependent mechanisms as well as through Let-7 independent mechanisms involving the targeting of mRNAs involved in cell metabolism, facilitating growth and transformation. Furthermore, IMP-1 is an invaluable executor of th LIN28B-Let-7 mediated actions. We will pursue this hypothesis through the following interrelated Specific Aims: (1) To elucidate the inter-relationship between LIN28B and c-MYC in intestinal epithelial biology~ (2) To evaluate the Let-7 dependent vs. the Let-7 independent effects of LIN28B in intestinal crypt biology, Paneth cell identity and transformation~ and (3) To evaluate the biological properties of IMP-1 in intestinal epithelial biology. In aggregate our innovative studies reveal new insights into how the LIN28B-Let-7-IMP-1 axis modulates intestinal epithelial homeostasis and aberrations, and starts to unravel new pathways, which in turn might have translational applications (diagnosis, prognosis and therapy).