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 毒液是一个复杂的特征，在整个生命树中都在超过200,000只动物中趋于发展，总计 大约约15-30％的动物生物多样性。毒液表型的患病率证明了其分子成功 并且研究其进化具有广泛的应用来了解同源组织的发展，这是 新型基因以及生物活性化合物调节和表达背后的分子机制。 相当大的毒液是精确医学的原型：引起高度特异性和直接的反应。 这些属性具有药物发现的工作，从而导致突破性的毒液衍生的疗法 条件，从糖尿病到心脏病再到疼痛。但是，毒液的全部潜力在医学和生物学中都 研究未开发。由于缺乏遗传操纵的稳健模型，因此出现了这种未满足的需求 毒液的发展以及毒液生物活性肽的调节和表达。 Holford Group的工作是第一个将Terebrid Venom辣椒描述为生物活性的作品 镇痛和抗肿瘤活性。但是，没有指导毒液和毒液如何在体内发展的原则， 我们和其他毒液研究人员刚刚刮擦了表面。我们需要模型系统来彻底改变研究毒液 腺体生物学，以便我们可以从根本上改变我们的产生，操纵和利用毒液武器库的方式。 头足类型育种计划提供了应对生物学和翻译所需的工具和模型 仍然无法接近的问题，例如：驱动掠夺性毒液表达的是什么 成分？我们可以用所需功能操纵特定毒素的产生，例如针对接收器的毒素 参与镇痛活动？基因工程，基因组学，转录组学和蛋白质组学的进步将允许 我们生成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 可以研究以探讨有关组织发育以及基因调节和表达的基本问题。 特别是：（1）确定与毒腺发育，维护和分泌有关的基因和蛋白质 跨潜水员头像类群。该目标将确定毒液唾液之间的进化基础 腺体和其他外分泌组织跨分类单元。 （2）追踪头足类唾液腺的发展。这个目标将 揭示了可以利用的遗传途径，以确定不同分类单元的毒腺的形成和功能。 （3）建立比较头足动物转基因模型。这个目标将建立转基因头足动物，使我们 为了优化毒液的实用性，以了解同源组织的发展，即新基因的起源， 以及生物活性化合物调节和表达背后的分子机制。 拟议的研究是PI的新方向，它是高风险高奖励的，并且将使不同的领域受益 和行业，包括发育性细胞和分子生物学以及药物发现与发育。大多数疾病， 像阿尔茨海默氏症或癌症一样具有复杂的特征，其在模型系统中的遗传表征对于寻找 有效的疗法。研究可靠的，培养的头足动物中毒液复杂性状的进化遗传学 系统将广泛影响NIH增强人类健康的使命的研究。