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The role of Hedgehog Signaling in gastric tissue repair and regeneration

Hedgehog信号传导在胃组织修复和再生中的作用

基本信息

批准号：
10044934
负责人：
Yana Zavros
金额：
$ 30.13万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044934
关键词：
Age Age-Months Aging Aspirin Bacterial Infections Biopsy Bone Marrow CD44 gene Cell Lineage Cell Surface Proteins Cells Chemotactic Factors Chief Cell Chimera organism Data Development Disease Duodenal Ulcer Elderly Environment Epidemiology Epithelial Epithelium Erinaceidae Event Gastric Acid Gastric Parietal Cells Gastric Tissue Gastric ulcer General Population Gland Goals Granulation Tissue Health Helicobacter Infections Helicobacter pylori Hemorrhage High Prevalence Hospitalization Human Immune Impairment Incidence Infection Infiltration Injury Knowledge Ligands Metaplasia Molecular Mus Myeloid Cells Natural regeneration Non-Steroidal Anti-Inflammatory Agents Organoids Outcome Patients Peptic Ulcer Perforation Pharmaceutical Preparations Play Population Process Protein Isoforms Proteins Publishing Recurrence Reporting Research Role SHH gene Site Stomach Testing Time Tissues Transplantation Ulcer Variant aged base experimental study healing hedgehog signal transduction impression macrophage mortality novel therapeutics older patient prevent receptor recruit repaired response response to injury smoothened signaling pathway spasmolytic polypeptide stem cell therapy stem cells targeted treatment therapeutic evaluation therapeutic target tissue regeneration tissue repair transcriptome transcriptome sequencing transdifferentiation transplant model wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT While it is established that the incidence of gastric ulcers in the elderly is primarily due to increased use of NSAIDs and other medications, and increased H. pylori infection, the tissue's ability to repair gastric injuries is impaired. Our impression that ulcers heal normally in the aged stomach is false. The available treatments for peptic ulcer are essentially based on gastric acid suppression with anti-secretory drugs and the eradication of H. pylori infection. Despite the evidence that shows ulcers and their complications are a burden that is focused in the elderly, there is a lack of knowledge as to the molecular mechanisms that disrupt repair even after H. pylori eradication within the aged stomach. The objectives of this proposal are to 1) develop an understanding for the process of gastric regeneration, and to then 2) identify the mechanism by which the basic aging process of the stomach leads to an epithelium incapable of repair in response to injury. The acquisition of such knowl- edge is the first step in a continuum of research required to achieve our long-term goal to understand the proc- ess of gastric epithelial repair in response to injury. The central hypothesis is that loss of Hedgehog signaling within the normal stem cell environment of the aged stomach results in impaired regeneration of the stomach in response to injury. The hypothesis has been formulated on the basis of preliminary data that show during re- pair of the stomach in response to ulceration there is the emergence of Spasmolytic Polypeptide/TFF2- Expressing Metaplasia (SPEM) cells at the base of ulcer margin. Our data suggest that SPEM represents the major reparative lineage responsible for wound healing after severe gastric ulcer injury. We have also identi- fied that the cell surface protein CD44, in particular its variant isoforms (CD44v), marks a population of cells within reparative SPEM glands that express Hedgehog receptor Patched (Ptch). Moreover, Hedgehog proteins Sonic Hedgehog (Shh) and Indian Hedgehog (Ihh) are key regulatory factors that play reparative roles in re- sponse to injury by regulating macrophage infiltration and CD44v expression, respectively. Guided by strong preliminary data, this hypothesis is tested by pursuing two specific aims: 1) what is the mechanism by which Hedgehog signaling regulates gastric epithelial repair? And, 2) what is the mechanism by which the aging process of the stomach leads to disrupted repair? The hypothesis will be tested using bone marrow chimeras, heterochronic and isochronic parabioses, a mouse injury/transplantation model using mouse- and human- derived gastric organoids and lineage mapping experiments. At the completion of these studies, we expect to define the molecular events that are crucial for the repair of the gastric epithelium. Outcomes from the pro- posed studies are expected to have significantly advanced our current knowledge of the mechanism by which aging leads to disrupted epithelial repair. The rationale that underlies the research proposed is to develop the potential for testing therapeutic target efficacy and other strategies, such as stem-cell therapy, for the regen- eration of the aged stomach.

项目概要/摘要虽然已确定老年人胃溃疡的发病率主要是由于增加使用非甾体抗炎药和其他药物，以及幽门螺杆菌感染增加，组织修复胃损伤的能力受损。我们认为老化的胃溃疡会正常愈合的印象是错误的。可用的治疗方法消化性溃疡主要基于使用抗分泌药物抑制胃酸和根除胃酸。幽门螺杆菌感染。尽管有证据表明溃疡及其并发症是人们关注的负担在老年人中，即使在幽门螺杆菌感染后，仍缺乏对破坏修复的分子机制的了解。根除老年胃内的幽门螺杆菌。该提案的目标是 1) 加深理解胃再生过程，然后2）确定基本衰老过程的机制胃的上皮细胞无法针对损伤进行修复。获得这样的知识边缘是实现我们理解过程的长期目标所需的连续研究的第一步胃上皮修复响应损伤的能力。中心假设是 Hedgehog 信号丢失老化胃的正常干细胞环境中会导致胃的再生受损对伤害的反应。该假设是根据重新评估期间显示的初步数据制定的。对胃部溃疡的反应是出现解痉多肽/TFF2- 溃疡边缘底部表达化生 (SPEM) 细胞。我们的数据表明 SPEM 代表负责严重胃溃疡损伤后伤口愈合的主要修复谱系。我们还确定了研究表明，细胞表面蛋白 CD44，特别是其变体同工型 (CD44v)，标记了细胞群在表达 Hedgehog 受体 Patched (Ptch) 的修复性 SPEM 腺体内。此外，刺猬蛋白 Sonic Hedgehog (Shh) 和 Indian Hedgehog (Ihh) 是在修复过程中发挥修复作用的关键调节因子。分别通过调节巨噬细胞浸润和 CD44v 表达来响应损伤。强者引导根据初步数据，该假设通过追求两个具体目标进行检验：1） Hedgehog信号调节胃上皮修复？并且，2）衰老的机制是什么？胃的过程导致修复中断？该假设将使用骨髓嵌合体进行测试，异时性和等时性联体共生，使用小鼠和人类的小鼠损伤/移植模型衍生胃类器官和谱系图谱实验。在完成这些研究后，我们期望定义对胃上皮修复至关重要的分子事件。亲的成果所提出的研究预计将显着提高我们目前对这一机制的认识衰老导致上皮修复受损。拟议研究的基本原理是开发测试治疗目标功效和其他策略（例如干细胞疗法）的潜力，以促进再生老化胃的排泄。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of parietal cell expression of Sonic hedgehog induces hypergastrinemia and hyperproliferation of surface mucous cells.

DOI：
10.1053/j.gastro.2009.11.002
发表时间：
2010-02
期刊：
Gastroenterology
影响因子：
29.4
作者：
Xiao C;Ogle SA;Schumacher MA;Orr-Asman MA;Miller ML;Lertkowit N;Varro A;Hollande F;Zavros Y
通讯作者：
Zavros Y

The Novel Role of Lgr5 as a Regulator of Cell Homeostasis and Disease of the Gastric Oxyntic Mucosa.

Lgr5 作为细胞稳态调节剂和胃含氧粘膜疾病的新作用。