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.

项目概要 再生医学的一个中心目标是了解细胞如何功能性地整合到现有组织中 恢复体内平衡和行为的一组〜6个物种的再生研究。 通过发现促进扩散的机制，在实现这一目标方面取得了相当大的进展， 然而，对这些机制的研究揭示了潜在的命运规范和新的细胞存活。 问题：如何限制组织重新模式以提供功能恢复和重建 了解生长和模式是如何受到限制的，并且没有疼痛过度生长。 相反，组织如何可控地退化将需要扩大这些现象发生的系统 经过检查，包括自然、循环和高度定型的再生和退化模型。 这样的系统——季节性繁殖鸣禽——提供了一个绝佳的机会来测试机械假设 生长和退化的过程以及分子和细胞水平的事件和结果如何影响更高的 该实验室使用两种不同的鸣禽：甘贝尔白冠鸟。 麻雀（Zonotrichia leugophrys gambelli）和驯养金丝雀（Serinus canaria Domestica）。 冠麻雀的优势在于具有季节性退化和再生的剧烈循环 控制歌唱行为的神经回路；详细介绍其自然历史和高水平的文献； 由于金丝雀品种在实验室中的天然丰富性和稳健性，因此易于进行实验分析， 每个人都有独特的歌唱能力和有据可查的遗传学，有望将历史联系起来 选择特定等位基因变体的再生形式和功能以及个体水平的可塑性 利用麻雀的自然和剧烈的退化-再生循环。 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）进行微调，以防止组织和行为过度退化，同时保持 利用严格的基因控制恢复体内平衡和随后的可塑性。 饲养员在选择金丝雀夸张的歌声时，这项工作的目的是确定金丝雀的多样化如何 行为源于对退化和再生之间平衡的改变，以及遗传如何 为了实现这些目标，该计划转化为细胞可塑性和新行为的出现。 将使用一套高度综合和互补的方法——包括药理学操作 自由行为的鸟类的完整神经回路；经典的细胞、分子和组织学分析； 最先进的基因组方法——探究细胞、分子和进化机制的调节 揭示组织的直接和最终机制。 重塑将为我们对肥大和退行性疾病的理解增加基础知识 并可能揭示在临床环境中替代丢失或受损组织的新方法。