MECHANISMS OF CHIEF CELL DEDIFFERENTIATION

主要细胞去分化的机制

• 批准号: 9329404
• 负责人: Jason C Mills
• 金额: $ 34.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329404
• 关键词: Address; Affect; Applications Grants; Autophagocytosis; Cell Cycle; Cell Line; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Chief Cell; Chronic; Cytoplasmic Granules; Data; Data Set; Databases; Development; Dose; Enzyme Precursors; Enzymes; Epithelial; FRAP1 gene; Gastric mucosa; Genes; Genetic; Genetic Transcription; Goals; Health; Helicobacter Infections; Helicobacter pylori; Human; In Vitro; Incidence; Infection; Inflammatory; Injury; Lesion; Light; Lysosomes; Malignant Neoplasms; Metaplasia; Metaplastic; Mitotic; Modeling; Molecular; Monomeric GTP-Binding Proteins; Multipotent Stem Cells; Mus; Organ; Organoids; Patient risk; Patients; Pharmaceutical Preparations; Process; Publishing; Recycling; Regulation; Risk; Role; Secretory Vesicles; Seminal; Signal Pathway; Signal Transduction; Specimen; Speed; Stem cells; Stomach; Tamoxifen; Testing; Time; cancer initiation; carcinogenesis; cell dedifferentiation; experimental study; genetic pedigree; human disease; human tissue; injury and repair; malignant stomach neoplasm; novel; pancreatic cell line; prevent; progenitor; programs; public health relevance; repaired; spasmolytic polypeptide; stemness; tissue repair; trafficking; transcription factor

 DESCRIPTION (provided by applicant): It has become clear in just the past two years that many mature cell lineages in digestive organs can dedifferentiate and re-enter the cell cycle to repair tissue damage. We and others have shown that post-mitotic cells can re-induce progenitor cell markers, re-enter the cell cycle, and can even serve as progenitors for other lineages. The dedifferentiation process carries a risk, however, as re-expressing progenitor cell genes is a form of cellular metaplasia. In states of chronic injury, like H. pylori infection in huan stomach, metaplasia continues indefinitely and increases risk for progression to cancer. Overall, cellular dedifferentiation presents a new paradigm for understanding tissue repair, "stemness", and cancer initiation. Our overarching goal is to understand the cellular and molecular mechanisms governing dedifferentiation. Here, we will focus on the earliest stages of dedifferentiation in gastric digestive-enzyme secreting zymogenic chief cells (ZCs). Our preliminary and published data will show that the first stage is engulfment of secretory granules by lysosomes and that lysosomal turnover of the digestive enzyme secretory granules (secretory apparatus "downscaling") must occur before progression to the next stages: metaplastic re- expression of progenitor cell genes and cell cycle re-entry. We will show the earliest molecular change in dedifferentiating ZCs is dramatically decreased expression of the bHLH transcription factor MIST1 (BHLHA15) and that deletion of Mist1 even in healthy ZCs is sufficient to induce lysosomal turnover of secretory granules. Finally, we will show that the only known transcriptional target of MIST1 that traffics lysosomes and is hence the most likely reason for the lysosomal attack on secretory granules when MIST1 is lost during dedifferentiation is the small GTPase, RAB26. Our aims are to: 1) determine the requirement/sufficiency for MIST1 in metaplasia downscaling; 2) determine if RAB26 affects flux through autophagy/mTOR signaling and whether it modulates granule destruction by lysosomes and/or autolysosomes; 3) a) determine if autophagic machinery is required for downscaling by inducing metaplasia following deletion in mature ZCs of the key autophagy genes Atg5 and Atg7 and b) to quantify autophagy/lysosome interaction with secretory granules in a database of human specimens where there are foci of ZCs undergoing dedifferentiation/metaplasia. Together the experiments will uncover for the first time the molecular mechanisms underlying the newly described cellular process of dedifferentiation and will have impact on human health because we will need to understand how metaplastic precursor lesions form from dedifferentiation of mature cells to be able to understand how to revert them and decrease risk for patients to progress to cancer.

 描述（由适用提供）：在过去的两年中，消化器官中的许多成熟细胞谱系已经变得清楚，可以去分化并重新进入细胞周期以修复组织损伤。我们和其他人表明，有丝分裂后细胞可以重新诱导祖细胞标记，重新进入细胞周期，甚至可以作为其他谱系的祖细胞。但是，去分化过程有风险，因为重新表达祖细胞基因是细胞化生的一种形式。在慢性损伤状态，例如Huan Stall中的幽门螺杆菌感染，Metaplasia无限期地持续，并增加了发展为癌症的风险。总体而言，细胞去分化提供了一种新的范式，以了解组织修复，“ Stemness”和Cancer启动。我们的总体目的是了解有关去分化的细胞和分子机制。在这里，我们将重点关注胃消化酶分泌的酶分泌酶促主要细胞（ZCS）的最早阶段。 Our preliminary and published data will show that the first stage is engulfment of secretory granules by lysosomes and that lysosomes and that lysosomal turnover of the digestive enzyme secretory granules (secretory apparatus "downscaling") must occur before progression to the next stages: metaplastic re-expression of progenitor cell genes and cell cycle re-entry.我们将显示去分化ZC的最早分子变化大大降低了BHLH转录因子MIST1（BHLHA15）的表达，即使在健康的ZC中，MIST1的缺失也足以诱导分离颗粒的溶酶体流动。最后，我们将证明，MIST1的唯一已知的转录目标是交通溶酶体，因此是在去分解过程中MIST1丢失时对分泌颗粒进行溶酶体攻击的最可能原因是小的GTPase Rab26。我们的目的是：1）确定降尺度降低的MIST1的要求/充分性； 2）确定RAB26是否通过自噬/MTOR信号传导影响通量，以及它是否通过溶酶体和/或自身溶血体调节颗粒的破坏； 3）a）确定在关键自噬基因ATG5和ATG7和ATG7和b）中删除后通过诱导的化生降低降低的自噬机械来量化自体/溶酶体与秘书摄入量的自体/溶血体的相互作用，而ZC/ZC的群体中的人类标本中的群体量很大。实验将首次揭示新描述的细胞去分化过程的分子机制，并将对人类健康产生影响，因为我们需要了解如何从成熟细胞的去分化中形成转移性前体病变，从而能够理解如何将其恢复并降低患者的风险，从而发展为癌症。