Genetic regulation of tissue regeneration

组织再生的基因调控

• 批准号: 10596111
• 负责人: Rachel Smith-Bolton
• 金额: $ 39.65万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596111
• 关键词: Acute; Animals; Back; Biological Models; Biology; Candidate Disease Gene; Cell Fate Control; Cells; Chronic Disease; Chronic Obstructive Pulmonary Disease; Cystic Fibrosis; Development; Diabetes Mellitus; Digit structure; Drosophila genus; Funding; Gene Expression; Gene Expression Profile; Genetic; Genomic approach; Genomics; Goals; Growth Factor; Heart Diseases; Human; Individual; Injury; Islets of Langerhans; Knowledge; Life Expectancy; Medical; Mission; Molecular; Myocardium; Natural regeneration; Outcome; Pathway interactions; Patients; Pattern; Proliferating; Public Health; Pulmonary alveolar structure; Quality of life; Regenerative Medicine; Regulation; Research; Signal Induction; Signal Transduction; Structure; Techniques; Tissues; Trauma; Traumatic injury; United States National Institutes of Health; Work; appendage; candidate identification; design; flexibility; gene regulatory network; genomic locus; human tissue; innovation; prevent; programs; protective factors; regenerative growth; response; side effect; tissue regeneration; transcription factor; wound response

Tissue damage caused by trauma or chronic illness reduces quality of life and shortens life expectancy. The ability to regulate the endogenous response to damage, and to induce regenerative growth, would have profound implications for the field of regenerative medicine. The Smith-Bolton lab has developed innovative techniques to: 1) induce tissue damage in hundreds of animals simultaneously, enabling the use of powerful Drosophila genetics to identify mechanisms that regulate tissue regeneration, and 2) isolate the regenerating tissue, ena- bling high-throughput genomic approaches to characterize the molecular mechanisms that underly regeneration control. The long-term goal of the Smith-Bolton lab is to understand how damaged tissue regenerates a func- tional structure. During the past five years, funded by NIH R01GM107140 “Regulation of Cell Fate and Patterning during Regenerative Growth”, the lab has used genetic and genomic techniques to 1) demonstrate that regen- eration signaling and unconstrained expression of regeneration growth factors have deleterious side effects, 2) identify several protective factors that prevent these unwanted outcomes, and 3) identify multiple mechanisms through which the magnitude and duration of regeneration signaling are tightly controlled. The purpose of this R35 MIRA application is to obtain stable and flexible funding to continue our successful and innovative work identifying the intricate pathways that control tissue regeneration. Important questions remain unanswered, such as 1) How do tissue-damage signals induce the changes in gene expression that carry out each step in regen- eration? 2) How does the regenerating tissue switch back to its normal patterning and gene expression profile? 3) Does regeneration recapitulate development, or are there regeneration-specific patterning controls? The re- search programs in the Smith-Bolton lab over the next five years will seek to achieve specific goals, including using genetic, genomic, and molecular techniques to: 1) identify the transcription factors and the genetic targets of those factors that constitute the gene regulatory networks that control individual steps in regeneration, 2) provide a detailed understanding of how key genomic loci are regulated after tissue damage, 3) elucidate the mechanism through which regenerating tissue returns to normal, and 4) identify additional regeneration-specific regulators of cell fate and patterning. When this work is complete, we will have a mechanistic understanding of how regeneration can derail cell fate, and the variety of mechanisms used to prevent catastrophic changes in gene expression after tissue damage. This work will have a critical positive impact because strategies developed to induce medically relevant regrowth of tissue after acute injury or chronic illness must account for deleterious side effects of pro-regeneration signals and incorporate protective factors to prevent aberrations. Furthermore, this work will identify candidate genes that can be targeted to manipulate specific aspects of the tissue damage response, while avoiding unwanted effects such as overstimulation of the wound response or unregulated pro- liferation, both in model systems and in humans.

创伤或慢性病造成的组织损伤降低了生活质量，缩短了预期寿命。这个 调节内源性损伤反应并诱导再生生长的能力，将具有深远的意义 对再生医学领域的影响。史密斯-博尔顿实验室已经开发出创新技术 为了：1)同时对数百种动物造成组织损伤，使强大的果蝇得以使用 遗传学，以确定调节组织再生的机制，以及2)分离再生组织，Ena- 用高通量基因组学方法研究再生不足的分子机制 控制力。史密斯-博尔顿实验室的长期目标是了解受损组织如何再生功能- 国家结构。在过去的五年中，由美国国立卫生研究院R01GM107140《细胞命运和图案化的调控》资助 在再生生长过程中，该实验室使用遗传和基因组技术1)证明了再生- 激活信号和不受限制地表达再生生长因子有有害的副作用，2) 确定防止这些不想要的结果的几个保护性因素，以及3)确定多种机制 通过它，再生信号的大小和持续时间受到严格控制。这样做的目的是 R35 Mira申请是为了获得稳定和灵活的资金，以继续我们成功和创新的工作 识别控制组织再生的错综复杂的途径。重要的问题仍然没有得到回答，比如 作为1)组织损伤信号如何引起基因表达的变化，这些变化执行再生的每一步- 再生组织如何转换回其正常的模式和基因表达模式？ 3)再生是否概括了发育，或者是否有再生特定的图案化控制？再一次- 未来五年，史密斯-博尔顿实验室的搜索计划将寻求实现具体目标，包括 使用遗传、基因组和分子技术：1)识别转录因子和遗传靶标 在构成基因调控网络的那些因素中，控制再生的各个步骤，2) 详细了解组织损伤后关键基因座是如何调节的，3)阐明 再生组织恢复正常的机制，以及4)确定额外的再生特异性 细胞命运和模式的调节者。当这项工作完成后，我们将有一个机械性的理解 再生如何能够改变细胞的命运，以及用来防止灾难性变化的各种机制 组织损伤后的基因表达。这项工作将产生关键的积极影响，因为制定了战略 在急性损伤或慢性疾病后诱导医学上相关的组织再生必须考虑有害的 它可以减少促再生信号的副作用，并结合保护性因素来防止畸形。此外， 这项工作将确定候选基因，这些基因可以作为靶点来操纵组织损伤的特定方面 反应，同时避免不想要的影响，如过度刺激伤口反应或不受调节的促进剂. 无论是在模型系统中还是在人类中，增殖都是如此。