Evolution of Developmental Regulatory Pathways

发育监管途径的演变

• 批准号: 7647122
• 负责人: RONALD E ELLIS
• 金额: $ 28.08万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647122
• 关键词: Address; Aging; Animal Model; Animals; Basic Science; Binding; Biomedical Research; Birds; CCL4 gene; Caenorhabditis elegans; Cell Death; Chromosome Mapping; Cloning; Complex; Data; Development; Disease; Employee Strikes; Enhancers; Evolution; F-Box Proteins; Female; Fogs; Funding; Future; Genes; Genetic; Genetic Screening; Genome; Habits; Hermaphroditism; Homologous Gene; Human; Influentials; Learning; Medical; MicroRNAs; Mind; Molecular Analysis; Molecular Cloning; Molecular Genetics; Natural Selections; Nematoda; Partner in relationship; Pathway interactions; Phylogeny; Physicians; Play; Process; Protein Binding; Proteins; RNA Interference; Regulator Genes; Regulatory Pathway; Reproductive Biology; Research; Role; SKP Cullin F-Box Protein Ligases; Scientist; Single Nucleotide Polymorphism Map; Spermatogenesis; Structure; Study models; System; Techniques; Textbooks; Time; Transgenic Animals; United States National Institutes of Health; Ursidae Family; Wing; Work; fighting; functional genomics; gene function; genome sequencing; interest; member; mutant; novel; research study; sex determination; sperm cell; theories; tool; trait

DESCRIPTION (provided by applicant): The advent of genome sequencing restored evolutionary studies to a central place in biomedical research, since they are essential for interpreting how information about regulatory pathways in model organisms might apply to humans. One of the big questions in the field is how these regulatory pathways evolve. Three factors make nematodes an excellent model for studying evolutionary processes. First, C. elegans is a major focus of study about reproductive biology, cell death, micro-RNAs, aging, and other subjects of interest to physicians. Second, the genomic and functional tools available for working with these animals are outstanding. Third, excellent traits are available for study. For example, hermaphrodite development evolved independently in the nematodes C. elegans and C. briggsae. This proposal describes experiments that use genetic and molecular techniques to learn how hermaphroditic development evolved in C. briggsae. Since hermaphrodite nematodes modulate the sex-determination pathway to allow XX animals to make sperm, this trait is ideal for learning how regulatory pathways change during evolution. So far, we have identified and cloned glf-1, which causes XX animals to develop as hermaphrodites, and glf-2, which acts downstream of glf-1. These genes are novel to C. briggsae, and critical to learning how hermaphrodite development originated. This project has three specific aims. The first is to screen for proteins that interact with GLF-1. Since GLF-1 is a member of a new class F-box proteins, its binding partners are the key to understanding how it controls development. The second aim is to clone and characterize glf-2, a new sex-determination gene that acts downstream of glf-1 to promote spermatogenesis. The third aim involves the use of enhancer and suppressor screens to identify additional genes that act in this pathway, and to characterize these genes. These genes would be candidates for future cloning and molecular analyses. Many genes cooperate to regulate how humans develop and fight disease. Much of the basic research funded by the NIH focuses on how these genes work by studying them in simple creatures. This project will elucidate how the functions of genes change during evolution, which could help scientists choose which creatures to study, and avoid mistaken inferences about their medical significance.

描述（由申请人提供）：基因组测序的出现使进化研究恢复到生物医学研究的中心地位，因为它们对于解释有关模式生物中的调控途径的信息如何适用于人类至关重要。该领域的一大问题是这些监管途径如何演变。三个因素使线虫成为研究进化过程的优秀模型。首先，线虫是生殖生物学、细胞死亡、微小RNA、衰老以及医生感兴趣的其他课题的主要研究焦点。其次，可用于研究这些动物的基因组和功能工具非常出色。第三，优秀的品质可供学习。例如，线虫 C. elegans 和 C. briggsae 中的雌雄同体发育是独立进化的。该提案描述了使用遗传和分子技术来了解 C. briggsae 雌雄同体发育如何进化的实验。由于雌雄同体线虫调节性别决定途径以允许 XX 动物产生精子，因此该特征非常适合了解进化过程中调节途径如何变化。到目前为止，我们已经鉴定并克隆了导致XX动物发育为雌雄同体的glf-1和作用于glf-1下游的glf-2。这些基因对于 C. briggsae 来说是新颖的，对于了解雌雄同体发育的起源至关重要。该项目有三个具体目标。第一个是筛选与 GLF-1 相互作用的蛋白质。由于 GLF-1 是新型 F-box 蛋白的成员，因此其结合伙伴是了解其如何控制发育的关键。第二个目标是克隆和表征glf-2，这是一种新的性别决定基因，在glf-1下游发挥作用，促进精子发生。第三个目标涉及使用增强子和抑制子筛选来识别在该途径中起作用的其他基因，并表征这些基因。这些基因将成为未来克隆和分子分析的候选基因。许多基因共同调节人类的发育和对抗疾病的方式。美国国立卫生研究院资助的大部分基础研究都集中在通过研究简单生物体内的这些基因如何发挥作用。该项目将阐明基因功能在进化过程中如何变化，这可以帮助科学家选择要研究的生物，并避免对其医学意义的错误推断。