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.

项目总结 再生医学的一个中心目标是了解细胞如何在功能上整合到现有组织中 恢复动态平衡和行为。一组~6个物种组织损伤后再生的研究 通过发现促进扩散的机制，朝着这一目标取得了相当大的进展， 命运规范，和新的细胞存活。然而，对这些机制的研究揭示了潜在的 问题：组织重建如何局限于提供功能修复和重建 动态平衡，没有有害的过度生长。要了解增长和模式是如何受到限制的，以及 相反，组织如何可控地退化将需要拓宽这些现象所在的系统 包括自然的、周期性的和高度定型的再生长和退化模型。一 这样的系统--季节性繁殖鸣禽--提供了检验机械假说的绝佳机会-- 生长和退化的ESES以及分子和细胞水平上的事件和结果如何影响更高- 水平解剖和行为。这个实验室使用了两种不同的鸣鸟：甘贝尔白冠鸣禽 麻雀(Zonotrichia Leugophrys Gambeli)和家养金丝雀(Serinus Canaria Home Tica)。白色- 冠雀在季节性退化和再生方面具有戏剧性的周期 控制歌唱行为的神经回路；详细描述他们自然历史的广泛文献；以及兴奋 由于其在实验室中的天然丰度和稳健性，因此易于进行实验分析。金丝雀繁育， 每个人都有独特的演唱能力和完善的遗传记录，有望将历史联系起来 对再生形式和功能以及个体水平可塑性的特定等位基因变异的选择 和人口数量。利用麻雀的自然和戏剧性的退化-再生循环 该提案旨在确定细胞死亡的方式：(I)影响新细胞的产生，以限制神经的总生长 组织和(Ii)微调，以防止过度退化的组织和行为，同时保持 恢复动态平衡和随后的可塑性的能力。利用实施的严格的基因控制 通过饲养者在金丝雀中选择夸张的鸣叫，这项工作旨在确定如何多样化 行为产生于对退化和再生之间的平衡的修改，以及如何遗传 变化转化为细胞的可塑性和新行为的出现。为了实现这些目标，这个项目 将使用一套高度整合和互补的方法-包括药物操作 自由活动鸟类的完整神经回路；经典的细胞、分子和组织学分析；以及状态- 最先进的基因组学方法--询问细胞、分子和进化调节机制 组织模式和动态平衡。揭示组织下的近端和终极机制 重塑将增加我们对肥大和退行性疾病的基础知识 并可能揭示在临床环境中替代丢失或受损组织的新方法。