Charting the evolutionary development of novel genes and the molecular mechanisms of gland tissue organizationin cephalopods

绘制头足类新基因的进化发展和腺体组织组织的分子机制

• 批准号: 10702230
• 负责人: Mande N. Holford
• 金额: $ 109.9万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702230
• 关键词: Alzheimer' s Disease; Analgesics; Animals; Behavior; Biodiversity; Biological; Biological Models; Biology; Breeding; Cellular biology; Cephalopoda; Complex; Development; Diabetes Mellitus; Disease; Disparate; Evolution; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Engineering; Genomics; Gland; Health; Heart Diseases; Human; Industry; Life; Maintenance; Malignant Neoplasms; Marine Invertebrates; Medicine; Mission; Modeling; Molecular; Molecular Biology; Nature; Organism; Pain; Pathway interactions; Peptides; Phenotype; Prevalence; Production; Proteins; Proteomics; Regulation; Research; Research Personnel; Salivary Glands; Surface; System; Therapeutic; Tissues; Toxin; Transgenic Model; Transgenic Organisms; Trees; United States National Institutes of Health; Venoms; Work; biological research; comparative; drug development; drug discovery; effective therapy; genetic manipulation; gland development; high reward; high risk; in vivo; novel; precision medicine; programs; prototype; receptor; response; success; tool; trait; transcriptomics; tumor

Abstract Venom is a complex trait that has convergently evolved in over 200,000 animals across the tree of life, totaling approximately ~15-30% of animal biodiversity. The prevalence of the venom phenotype demonstrates its molecular success and studying its evolution has broad applications to understanding the development of homologous tissues, the origins of novel genes, and the molecular mechanisms behind the regulation and expression of bioactive compounds. Considerably, venoms are the prototype of precision medicine: inducing a highly specific and immediate response. These attributes have fueled drug discovery efforts, leading to breakthrough venom-derived therapeutics for a wide range of conditions, from diabetes to heart disease to pain. However, the full potential of venom, in both medicine and biological research, is untapped. This unmet need arises because of the lack of robust models for genetically manipulating the development of venom glands and regulation and expression of venom bioactive peptides. The work of the Holford group was the first to characterize terebrid venom peptides as bioactive in mitigating analgesic and antitumor activity. However, without guiding principles for how venoms and venom glands develop in vivo, we, and other venom researchers, have just scratched the surface. We need model systems to revolutionize the study venom gland biology, so that we can radically transform how we generate, manipulate, and utilize venom arsenals. The cephalopod breeding program provide the tools and models necessary to tackle biological and translational questions that have remained unapproachable, such as: What drives the expression of predatory versus defensive venom components? Can we manipulate the production of specific toxins with a desired function, such as those targeting receptors involved in analgesic activity? Advancements in genetic engineering, genomics, transcriptomics, and proteomics will allow us to generate the first marine invertebrate transgenic cephalopod organisms that produce venom in specialized glands that can be investigated to explore fundamental questions about tissue development and gene regulation and expression. Specifically, we will: (1) Determine genes and proteins relevant to venom gland development, maintenance, and secretion across diverse cephalopod taxa. This objective will determine the evolutionary underpinnings between venom salivary glands and other exocrine tissues across taxa. (2) Trace the development of cephalopod salivary glands. This objective will reveal genetic pathways that can be leveraged to determine the formation and function of venom gland from diverse taxa. (3) Establish comparative cephalopod transgenic models. This objective will establish transgenic cephalopods allowing us to optimize the utility of venom glands for understanding the development of homologous tissues, the origins of novel genes, and the molecular mechanisms behind the regulation and expression of bioactive compounds. The proposed research is a new direction for the PI that is high risk-high reward, and will benefit disparate fields and industries, including developmental cellular and molecular biology and drug discovery and development. Most diseases, like Alzheimer or cancer have complex traits whose genetic characterization in model systems have been essential to finding effective therapies. Studying the evolutionary genetics in the complex trait of venom in a reliably, cultured cephalopod system will broadly impact research towards the NIH’s mission of enhancing human health.

抽象的 毒液是一种复杂的特征，在生命之树上超过 200,000 种动物中共同进化而来，总计 毒液表型的普遍性证明了其分子成功。 研究其进化对于理解同源组织的发育、生物体的起源具有广泛的应用 新基因，以及生物活性化合物调节和表达背后的分子机制。 值得注意的是，毒液是精准医学的原型：诱导高度特异性和即时的反应。 这些特性推动了药物发现工作，为广泛的毒液衍生疗法带来了突破性进展 然而，毒液在医学和生物学方面的全部潜力。 由于缺乏稳健的基因操纵模型，因此出现了这种未得到满足的需求。 毒腺的发育以及毒液生物活性肽的调节和表达。 霍尔福德小组的工作是第一个将三足动物毒液肽描述为具有缓解作用的生物活性的工作。 然而，如果没有毒液和毒腺在体内如何发育的指导原则， 我们和其他毒液研究人员刚刚触及表面，我们需要模型系统来彻底改变毒液研究。 腺体生物学，以便我们能够从根本上改变我们产生、操纵和利用毒液库的方式。 头足类动物育种计划提供了解决生物学和转化问题所需的工具和模型 仍然无法解决的问题，例如：是什么驱动了掠夺性和防御性毒液的表达 我们能否操纵具有所需功能的特定毒素的产生，例如针对受体的毒素 涉及镇痛活性？基因工程、基因组学、转录组学和蛋白质组学的进步将允许 我们培育出第一个海洋无脊椎动物转基因头足类生物，它们在专门的腺体中产生毒液 可以研究有关组织发育以及基因调控和表达的基本问题。 具体来说，我们将：（1）确定与毒腺发育、维持和分泌相关的基因和蛋白质 这一目标将确定毒液唾液之间的进化基础。 (2) 追踪头足类唾液腺的发育。 揭示可用于确定不同类群毒腺的形成和功能的遗传途径。 (3)建立比较头足类转基因模型这一目标将建立转基因头足类动物，使我们能够。 优化毒腺的用途，以了解同源组织的发育、新基因的起源， 以及生物活性化合物调节和表达背后的分子机制。 本研究为PI的一个新方向，高风险高回报，将惠及不同领域 和工业，包括发育细胞和分子生物学以及大多数疾病的发现和开发。 像阿尔茨海默病或癌症一样具有复杂的特征，其模型系统中的遗传特征对于发现这些特征至关重要 研究可靠的培养头足类动物毒液复杂特征的进化遗传学。 系统将广泛影响 NIH 增强人类健康使命的研究。