Mechanisms of cyclical degeneration and regeneration in an avian model system

鸟类模型系统的周期性退化和再生机制

• 批准号: 10714528
• 负责人: TRACY ALISON LARSON
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714528
• 关键词: Anatomy; Behavior; Biological Models; Birds; Breeding; Cell Death; Cell Survival; Cells; Clinical; Competence; Crowns; Degenerative Disorder; Equilibrium; Event; Generations; Genetic; Genomic approach; Goals; Growth; Histologic; Homeostasis; Hypertrophy; Individual; Knowledge; Link; Literature; Modeling; Modification; Molecular; Mutation; Natural History; Natural regeneration; Nerve Regeneration; Outcome; Pathologic; Pattern; Population; Proliferating; Public Health; Regenerative Medicine; Regenerative research; Research; Seasonal Variations; Seasons; Serinus; Songbirds; Sparrows; Specific qualifier value; Stereotyping; System; Testing; Tissues; Translating; Vertebrates; Work; experimental analysis; functional restoration; genetic variant; insight; neural circuit; neural growth; novel; pharmacologic; prevent; programs; regenerative; repaired; tissue degeneration; tissue regeneration

PROJECT SUMMARY A central goal of regenerative medicine is to understand how cells functionally integrate into existing tissues to restore homeostasis and behavior. Studies of regeneration following tissue damage in a group of ~6 species have made considerable advances towards this goal by uncovering mechanisms that promote proliferation, fate specification, and new cell survival. Pursuing these mechanisms, however, has revealed an underlying problem: how tissue re-patterning is limited to provide functional restoration and the re-establishment of homeostasis without detrimental overgrowth. To understand how growth and patterning are limited, and conversely, how tissues regress controllably will require broadening the systems in which these phenomena are examined to include models of natural, cyclical and highly stereotyped re-growth and degeneration. One such system – seasonally breeding songbirds – offers an outstanding opportunity to test mechanistic hypoth- eses of growth and degeneration and how events and outcomes at molecular and cellular levels impact higher- level anatomy and behavior. This lab makes use of two different songbird species: Gambel’s white-crowned sparrow (Zonotrichia leugophrys gambelli) and the domesticated canary (Serinus canaria domestica). White- crowned sparrows are advantageous in having dramatic cycles of seasonal degeneration and regeneration of the neural circuit that controls singing behavior; an extensive literature detailing their natural history; and high tractability for experimental analyses due to their natural abundance and robustness in the lab. Canary breeds, each having unique singing abilities and well-documented genetics, promise the ability to link historical selection for particular allelic variants to regenerative form and function, and plasticity at the level of individuals and populations. Exploiting the natural and dramatic degeneration–regeneration cycles in sparrows this proposal aims to determine how cell death: (i) influences generation of new cells to limit total growth of neural tissue and (ii) is finely tuned to prevent excessive degeneration of tissue and behavior while maintaining competency for a return to homeostasis and subsequent plasticity. Exploiting the tight genetic control imposed by breeders in selecting for exaggerated singing in canaries, the work aims to determine how diversification of behavior arose from modifications to the balance between degeneration and regeneration, and how genetic changes translate to cellular plasticity and emergence of novel behavior. Towards these goals, this program will use a highly integrative and complementary set of approaches – including pharmacological manipulations of intact neural circuits in freely behaving birds; classic cellular, molecular, and histological analyses; and state- of-the-art genomic approaches – to interrogate the cellular, molecular, and evolutionary mechanisms regulating tissue patterning and homeostasis. Uncovering proximate and ultimate mechanisms underlying tissue remodeling will add foundational knowledge to our understanding of hypertrophy and degenerative diseases and may reveal new ways by which lost or damaged tissues can be replaced in a clinical context.

项目摘要 再生医学的一个核心目标是了解细胞如何将功能整合到现有时间到 恢复体内平衡和行为。一组6种的组织损伤后再生的研究 通过发现促进扩散的机制，已经取得了长足的进步 命运规格和新的细胞存活。但是，追求这些机制已经揭示了基本的 问题：如何重新制作组织的限制以提供功能恢复和重新建立 体内稳态而没有有害的过度生长。了解增长和模式的有限，以及 相反，组织如何回归控制将需要扩大这些现象的系统 检查以包括天然，周期性和高度定型的重新增长和变性的模型。一 这种系统（季节性繁殖鸣禽）为测试机械假设提供了绝佳的机会 - 生长和变性的杂货以及分子和细胞水平的事件和结果如何影响较高的 解剖和行为水平。该实验室利用了两种不同的歌曲鸟：甘贝尔的白冠 Sparrow（Zonotrichia leugophrys gambelli）和驯养的金丝雀（Serinus canaria fimdera）。白色的- 冠状麻雀在具有季节性变性和再生的戏剧性周期方面是有利的 控制唱歌行为的神经电路；广泛的文献详细介绍了他们的自然历史；和高 由于实验室中的自然抽象和鲁棒性，实验分析的障碍性。金丝雀品种， 每个都具有独特的歌唱能力和有据可查的遗传学，承诺能够将历史链接起来 选择特定的Allic变体对再生形式和功能，以及个体水平的可塑性 和人口。利用麻雀中的自然和戏剧性变性 - 再生周期 建议旨在确定细胞死亡的方式：（i）影响新细胞的产生以限制神经元的总生长 对组织和（ii）进行细微调整以防止组织和行为的过度变性 重返体内平衡和随后的可塑性的能力。利用施加的严格遗传控制 通过呼吸选择夸张的金丝雀，该作品旨在确定多元化的多样化 行为从变化到变性与再生之间的平衡以及遗传如何 变化转化为细胞可塑性和新型行为的出现。实现这些目标，该计划 将使用高度集成和完整的方法 - 包括药物操纵 自由行为的鸟类完整的神经元电路；经典的细胞，分子和组织学分析；和国家 - ART基因组方法 - 询问调节的细胞，分子和进化机制 组织模式和稳态。揭示组织的近端和最终机制 重塑将为我们对肥大和退化性疾病的理解增加基础知识 并可能揭示了可以在临床背景下更换损失或损坏的组织的新方法。