Genetic regulation of tissue regeneration

组织再生的基因调控

• 批准号: 10204636
• 负责人: Rachel Smith-Bolton
• 金额: $ 42.3万
• 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/10204636
• 关键词: Acute; Animals; Back; Biological Models; Biology; Candidate Disease Gene; Cell Fate Control; Cells; Chronic Disease; Chronic Obstructive Airway 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; Lung; Medical; Mission; Molecular; Myocardium; Natural regeneration; Outcome; Pathway interactions; Patients; Pattern; Public Health; Quality of life; Regenerative Medicine; Regulation; Regulator Genes; Research; Signal Transduction; Structure; Techniques; Tissues; Trauma; Traumatic injury; United States National Institutes of Health; Work; appendage; design; flexibility; 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.

由创伤或慢性疾病引起的组织损伤降低了生活质量并缩短了预期寿命。的 调节对损伤的内源性反应和诱导再生生长的能力，将对人类的健康产生深远的影响。 对再生医学领域的影响。史密斯-博尔顿实验室开发了创新技术 1）同时在数百只动物中诱导组织损伤，从而能够使用强大的果蝇 遗传学，以确定调节组织再生的机制，以及2）分离再生组织， bling高通量基因组方法来表征再生的分子机制 控制史密斯-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。在过去的五年里，由NIH R 01 GM 107140“细胞命运和模式的调节”资助， 在再生生长过程中，实验室使用遗传和基因组技术来1）证明再生， 再生信号传导和再生生长因子的不受约束的表达具有有害的副作用，2） 确定几个保护因素，防止这些不必要的结果，和3）确定多种机制 通过其再生信号的幅度和持续时间被严格控制。这样做的目的 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复杂途径。重要的问题仍然没有答案，例如 1）组织损伤信号如何诱导基因表达的变化，这些变化执行再生中的每一步， eration？2)再生的组织如何切换回正常的模式和基因表达谱？ 3)再生是否重演了发展，或者有再生特定的模式控制？重新 史密斯-博尔顿实验室在未来五年内的研究计划将寻求实现特定的目标，包括 利用遗传学、基因组学和分子技术：1）鉴定转录因子和遗传靶点 这些因素构成了基因调控网络，控制再生的各个步骤，2） 提供组织损伤后关键基因组位点如何调节的详细理解，3）阐明 再生组织通过其恢复正常的机制，以及4）鉴定额外的再生特异性 细胞命运和模式的调节器。当这项工作完成后，我们将对 再生是如何破坏细胞命运的，以及用于防止细胞发生灾难性变化的各种机制。 组织损伤后的基因表达。这项工作将产生至关重要的积极影响， 为了在急性损伤或慢性疾病后诱导组织的医学相关的再生长，必须考虑有害的 副作用的促再生信号和纳入保护因素，以防止畸变。此外，委员会认为， 这项工作将确定候选基因，这些基因可以被靶向以操纵组织损伤的特定方面。 反应，同时避免不必要的影响，如过度刺激伤口反应或不受调节的促反应， 无论是在模型系统还是在人类中。