RUI: Identifying reproductive roles for the Super-conserved Receptors Expressed in Brain (SREB) G protein-coupled receptor family using novel agonists and a comparative fish model

SREB（Super-conserved Receptors Expressed in Brain）是脊椎动物中的一类激素受体蛋白，其功能尚不清楚。这种知识差距源于缺乏与细胞表面的SREB结合的经验证的激素。以前的研究支持SREB在大脑，肠道和性腺中的功能作用，这些功能可能在动物中保留。该项目应用新型人工合成的分子，已知这些分子与三种鱼类卵巢中的SREB受体结合，以评估SREB在生殖中的功能。基于先前鉴定的遗传差异选择这些种属，导致这些种属中SREB亚型的不同谱。结果将在鱼类物种之间进行比较，以确定独特和共同的功能。由此产生的SREB功能的理解可能为未来在动物繁殖和水产养殖中的商业应用提供基础。这项研究将产生数据库，以促进缅因州西部农村地区的本科生和高中生在生物信息学方面的研究经验，该地区的第一代大学生比例很高。当地高中教师将接受培训，以便在课堂上使用这些数据库，并开发独立的生物信息学模块供可持续使用。这些教育活动作为一个可扩展的模式，将生物信息学培训带到服务不足的学生群体，促进生物技术劳动力的发展。此外，通过与佛罗里达大学的两名研究人员的合作，该项目将有助于培养一名研究生和博士后研究员。最近开发的孤儿G蛋白偶联受体家族SREB的新型特异性激动剂使人们能够采用新的方法来了解受体功能的生理机制。两种合成和验证的激动剂分子正在与潜在的内源性配体（phoenixin）结合使用，用于体外卵巢治疗和三种遗传功能鱼类的RNA测序：斑马鱼（Danio rerio），mummichog（Fundulus heteroclitus）和河豚（Dichotomyctere nigroviridis）。这些物种中的每一个都表现出不同的SREB受体互补，这使得比较转录组学方法能够识别整个家族中保守的生殖功能以及SREB成员特异性效应。这些方法将与类固醇定量和RNAScope结合使用，以分别鉴定与SREB基因表达相关的生殖激素变化和特定性腺细胞类型。这种比较多物种模型的发展影响了未来生殖以外的SREB研究，例如SREB也涉及保守功能的大脑和肠道研究。该项目由BIO-IOS-生理机制和生物力学计划以及刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

SREBs (Super-conserved Receptors Expressed in Brain) are a group of hormone receptor proteins in vertebrate animals whose function is poorly understood. This knowledge gap stems from a lack of verified hormones that bind to SREBs on the surface of cells. Previous studies have supported functional roles for SREBs in the brain, gut, and gonads that may be conserved in animals. This project applies novel, artificially synthesized molecules that are known to bind to SREB receptors in ovaries of three fish species to assess SREB function in reproduction. The species were chosen based on previously identified genetic differences resulting in different profiles of SREB subtypes across these species. Results will be compared among the fish species to identify unique and shared functions. The resulting improved understanding of SREB functions may provide a foundation for future commercial applications in animal reproduction and in aquaculture. The research will generate databases that will foster undergraduate and high-school student research experiences in bioinformatics in rural western Maine, which has a high proportion of first-generation college students. Local high-school teachers will be trained to use these databases in their classes and to develop independent bioinformatics modules for sustainable use. These educational activities serve as a scalable model to bring bioinformatics training to under-served student populations, contributing to biotechnology workforce development. In addition, through a collaboration with two researchers at the University of Florida, the project will contribute to training of a graduate student and post-doctoral fellow.The recent development of novel and specific agonists for the orphan G protein-coupled receptor family SREB has enabled new approaches to understand the physiological mechanisms of receptor function. Two synthesized and validated agonist molecules are being used in combination with a potential endogenous ligand (phoenixin) in in vitro ovary treatments and RNA-sequencing of three genetically enabled fish species: zebrafish (Danio rerio), mummichog (Fundulus heteroclitus), and pufferfish (Dichotomyctere nigroviridis). Each of these species exhibits a different complement of SREB receptors, which enables comparative transcriptomic approaches to identify both conserved reproductive functions across the family as well as SREB member-specific effects. These methods will be used in combination with steroid quantifications and RNAScope to identify reproductive hormone changes and specific gonadal cell types associated with SREB gene expression, respectively. The development of this comparative multispecies model impacts future SREB studies beyond reproduction, such as investigations in the brain and gut where SREBs have also been implicated in conserved functions. This project is jointly funded by the BIO-IOS-Physiological Mechanisms and Biomechanics Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.