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.

摘要 毒液是一种复杂的特征，在生命之树上的20多万种动物中逐渐进化， 约占动物生物多样性的15-30%。毒液表型的流行证明了它在分子上的成功 研究它的进化对于理解同源组织的发育、 新基因，以及生物活性化合物调控和表达背后的分子机制。 相当大的程度上，毒液是精准医疗的原型：诱导高度特异性和即时反应。 这些属性推动了药物发现的努力，导致突破性的毒液衍生疗法的广泛应用。 从糖尿病到心脏病再到疼痛。然而，毒液在医学和生物学上的全部潜力 研究，未开发。这种未满足的需求的出现是因为缺乏用于基因操纵的鲁棒模型。 毒腺的发育及蛇毒活性肽的调控与表达。 Holford小组的工作是第一个将terebrid毒液肽描述为具有减轻 镇痛和抗肿瘤活性。然而，由于没有指导原则，毒液和毒腺如何在体内发展， 我们和其他的毒液研究者，才刚刚触及表面。我们需要模型系统来彻底改变研究毒液 腺体生物学，这样我们就可以从根本上改变我们如何产生，操纵和利用毒液库。 头足类动物育种计划提供了必要的工具和模型，以解决生物和翻译 这些问题仍然无法解决，例如：是什么驱动了捕食性毒液与防御性毒液的表达 组件？我们能否操纵特定毒素的生产，使其具有所需的功能，例如那些靶向受体的毒素 与镇痛作用有关吗基因工程、基因组学、转录组学和蛋白质组学的进步将使 我们创造了第一个海洋无脊椎动物转基因头足类生物，这种生物在专门的腺体中产生毒液， 可以用来探索有关组织发育和基因调控及表达的基本问题。 具体而言，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 不同的头足类动物。这一目标将确定毒液唾液 腺体和其他外分泌组织。(2)追踪头足类动物唾液腺的发展。这一目标将 揭示了可以用来确定不同分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动物模型。这一目标将建立转基因头足类动物， 优化毒腺的效用，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控和表达背后的分子机制。 该研究为高风险高回报的PI研究提供了一个新的方向，将对不同的领域产生积极的影响 和产业，包括发育细胞和分子生物学以及药物发现和开发。大多数疾病， 像阿尔茨海默病或癌症具有复杂的特征，其在模型系统中的遗传特征对于发现 有效的治疗。研究进化遗传学在复杂性状的毒液在一个可靠的，培养的头足类动物 该系统将广泛地影响研究，以实现国家卫生研究院的使命，提高人类健康。