Regulation of Cell Fate and Patterning During Regenerative Growth

再生生长过程中细胞命运和模式的调节

• 批准号: 9199102
• 负责人: Rachel Smith-Bolton
• 金额: $ 32.09万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199102
• 关键词: Ablation; Acute; Affect; Amphibia; Amputation; Animal Model; Animals; Biochemical; Biological Models; Biology; Body part; Cell Fate Control; Cell Maintenance; Cells; Choristoma; Chronic Disease; Chronic Obstructive Airway Disease; Cystic Fibrosis; Data; Development; Developmental Gene; Diabetes Mellitus; Digit structure; Drosophila genus; Embryo; Ensure; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Growth; Heart Diseases; Injury; Islets of Langerhans; Knowledge; Laboratories; Leg; Life Expectancy; Limb structure; Lung; MAPK8 gene; Maintenance; Manuals; Maps; Medical; Methods; Mission; Molecular; Mutation; Myocardium; Natural regeneration; Normal tissue morphology; Organ; Organism; Osteoblasts; Outcome; Patients; Pattern; Process; Public Health; Quality of life; Research; Signal Transduction; Specific qualifier value; Structure; System; Techniques; Testing; Tissues; Trauma; Traumatic injury; United States National Institutes of Health; Wing; Work; Zebrafish; appendage; base; blastema; design; experimental study; human tissue; improved; innovation; mutant; novel; public health relevance; regenerative; temporal measurement; tissue regeneration; tool; transcriptome

 DESCRIPTION (provided by applicant): Many organisms are able to regenerate whole limbs and portions of tissues and organs after amputation or significant damage. However, the molecular mechanisms that ensure maintenance of cell fate and proper re- patterning of the regenerating structure are unknown. The long-term goal is to understand how damaged tissue regenerates a functional body part. The overall objective of this proposal is to identify the developmental and novel patterning processes that are critical for proper formation of the regenerated Drosophila imaginal wing, an ideal model system because of the simplicity of the tissue, as well as its genetic tractability, well- characterized development, and wealth of available experimental tools. The central hypothesis is that regeneration resembles development in some ways, but also employs alternate mechanisms to maintain or establish patterning and cell fate. This hypothesis was formulated based on preliminary data generated in laboratory of the applicant; including mutations identified in a genetic screen that specifically affect patterning during regeneration, not development. The rationale for the proposed research is that identification of patterning mechanisms required during regeneration has the potential to guide efforts to enable and manipulate regeneration in human tissues that normally do not regrow after damage. This proposed work will be accomplished through the following specific aims: 1) Characterize patterning during regeneration with high spatial and temporal resolution; 2) Determine the regeneration-specific mechanism through which taranis maintains posterior cell identity; and 3) Identify additional regeneration-specific patterning mechanisms. Under the first aim, repatterning during regeneration will be mapped in fine detail by following changes in expression of known patterning genes and carrying out transcriptional profiling of the regeneration blastema. Under the second aim, the mechanism through which taranis ensures maintenance of engrailed expression and posterior cell fate during regeneration will be determined, using feasible genetic and biochemical approaches. Under the third aim, new genes and mechanisms that regulate cell fate and patterning during regeneration will be identified using two complementary approaches: 1) continuation of the already successful genetic screen and characterization of patterning mutants, and 2) characterization of regeneration genes identified through transcriptional profiling of purified blastema cells. This approach is innovative because it uses the full power of Drosophila genetics as well as novel cellular techniques to identify genes important for cell fate and patterning during regeneration. This re- search will be significant because it will identify novel, regeneration-specific molecular mechanisms that ensure regrowth of a functional structure after extensive tissue loss. Ultimately this improved understanding of regeneration has the potential to enable regrowth of damaged tissues, organs and appendages that do not normally regenerate.

 描述(申请人提供)：许多生物能够在截肢或严重损伤后再生完整的四肢和部分组织和器官。然而，确保维持细胞命运和适当重建再生结构的分子机制尚不清楚。长期目标是了解受损组织是如何再生身体功能部位的。这项建议的总体目标是确定对再生的果蝇想象翅膀的正确形成至关重要的发育和新的图案化过程，这是一个理想的模型系统，因为组织简单，以及它的遗传易操纵性、发育的良好特征和丰富的可用实验工具。中心假说是，再生在某些方面类似于发育，但也使用另一种机制来维持或建立图案和细胞命运。这一假设是基于申请者实验室中产生的初步数据提出的；包括在基因筛查中发现的突变，这些突变专门影响再生期间的图案，而不是发育。这项拟议研究的基本原理是，识别再生过程中所需的图案化机制有可能指导在人体组织中实现和操纵再生的努力，这些组织通常在损伤后不会再生长。这项拟议的工作将通过以下具体目标来完成：1)以高空间和时间分辨率表征再生过程中的图案化；2)确定Taranis维持后部细胞特性的再生特定机制；以及3)确定其他再生特定图案化机制。在第一个目标下，通过跟踪已知图案基因表达的变化和对再生胚泡进行转录图谱，将详细地绘制再生过程中的重新图案。在第二个目标下，将利用可行的遗传和生化方法来确定Taranis在再生过程中确保内化表达和后生细胞命运的机制。在第三个目标下，将使用两种互补的方法来确定在再生过程中调节细胞命运和模式形成的新基因和机制：1)继续已经成功的遗传筛选和模式突变的特征，以及2)通过纯化的胚泡细胞的转录图谱确定再生基因的特征。这种方法是创新的，因为它利用了果蝇遗传学的全部力量以及新的细胞技术来识别对再生过程中细胞命运和模式至关重要的基因。这项研究将具有重要意义，因为它将识别新的、特定于再生的分子 确保功能结构在广泛的组织丢失后重新生长的机制。最终，这种对再生的更好的理解有可能使受损的组织、器官和附件再生，这些组织、器官和附件通常不会再生。