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， 恢复体内平衡和行为。六种植物组织损伤后再生的研究 通过揭露促进扩散的机制，在实现这一目标方面取得了相当大的进展， 命运规范和新细胞存活。然而，对这些机制的研究揭示了一个潜在的 问题：组织重新形成图案如何被限制于提供功能恢复和重建 体内平衡，没有有害的过度生长。为了理解生长和模式是如何被限制的， 相反，组织如何可控地退化，需要拓宽这些现象所处的系统 包括自然的、周期性的和高度定型的再生长和退化模型。一 这种系统--季节性繁殖鸣禽--提供了一个极好的机会来检验机械假说， 以及分子和细胞水平上的事件和结果如何影响更高的 水平解剖和行为。这个实验室使用了两种不同的鸣禽： 麻雀（Zonotrichia leugophrys gambelli）和家养金丝雀（Serinus canaria arthritica）。白色- 冠雀的优势在于，它们具有季节性退化和再生的戏剧性周期， 控制歌唱行为的神经回路;详细描述其自然历史的大量文献;以及高 由于其在实验室中的天然丰富性和鲁棒性，因此易于实验分析。金丝雀品种， 每一种都有独特的歌唱能力和有据可查的遗传基因，保证了将历史联系起来的能力。 选择特定的等位基因变异体以再生形式和功能，以及个体水平的可塑性 和人口。利用麻雀自然和戏剧性的退化再生周期， 该提案旨在确定细胞死亡如何：（i）影响新细胞的生成以限制神经细胞的总生长 组织和（ii）被精细地调节以防止组织和行为的过度退化，同时维持 恢复体内平衡和随后的可塑性的能力。利用严格的基因控制 通过饲养员在选择金丝雀夸张的歌声，这项工作的目的是确定如何多样化， 行为产生于对退化和再生之间平衡的修改，以及遗传 变化转化为细胞可塑性和新行为的出现。为了实现这些目标，该计划 将使用一套高度综合和互补的方法-包括药理学操作 完整的神经回路在自由行为的鸟类;经典的细胞，分子和组织学分析;和状态- 最先进的基因组方法-询问细胞，分子和进化机制调节 组织模式和体内平衡。揭示组织下的近端和最终机制 重塑将增加我们对肥大和退行性疾病的理解的基础知识 并且可以揭示在临床环境中可以替换丢失或受损组织的新方法。