Mechanisms of Developmental Fidelity

发展忠诚度机制

• 批准号: 8954933
• 负责人: Joel H. Rothman
• 金额: $ 18.07万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8954933
• 关键词: Animals; Apoptosis; Automobile Driving; Caenorhabditis elegans; Cell Death; Cell Proliferation; Cell division; Cells; Cessation of life; Complex; Congenital Abnormality; Decision Making; Defect; Development; Developmental Process; Disasters; Embryo; Ensure; Environment; Event; Exploratory/Developmental Grant; Face; Frequencies; Genetic; Genetic Variation; Genome; Gonadal structure; Growth; Handedness; Human; Human Development; Inbreeding; Individual; Laws; Lead; Left; Length; Longevity; Malignant Neoplasms; Modeling; Molecular; Molecular Genetics; Nematoda; Neurodegenerative Disorders; Neurons; Noise; Operating System; Organ; Outcome; Output; Parents; Pregnancy; Probability; Process; Quality Control; Quantitative Trait Loci; Recombinants; Sensory; Structure; System; Tail; Variant; base; egg; genome sequencing; germline stem cells; high risk; insight; male; prevent; public health relevance; restraint; success; trait; zygote

 DESCRIPTION (provided by applicant): Developing embryos face vast numbers of parallel and sequential decisions each that is confronted with fluctuating environments and molecular "noise," and is thus fraught with a certain rate of error. While quality control systems that corret decision-making errors must be pervasive and are critical for human development, almost nothing is known about them. The hypothesis driving the proposed studies is that there exist quality control systems operating during development that ensure high-fidelity outcomes and that such systems may function across disparate developmental processes. We will avail of the highly reproducible development of C. elegans to investigate the mechanisms that regulate developmental fidelity. We found that C. elegans males show frequent "errors" in the activation of programmed cell death (PCD) during formation of the tail ray sensory structures and in the left-right (L/R) orientation of the major organs and that the propensity for these errors differs widely between different wild isolates (isotypes). Isotypes with high error rates in these two processes ("low-fidelity" strains) also show high variance in other processes, including germline stem cell proliferation and L1 larval length. In contrast, a strain with low error rates ("high-fidelity") in the former traits also shows low variance in the latter. We propose to unveil the molecular genetic basis for stochastic PCD and errors in L/R handedness and to investigate whether the fidelity of different developmental processes might be influenced by common mechanisms, through two aims. In Aim 1, we will investigate whether variation in fidelity is fully independent or significantly co-varies across several developmental processes by analyzing errors in disparate developmental processes across 97 isotypes and recombinant inbred lines (RILs) derived from "high-" and "low-fidelity" isotypes. We will evaluate whether fidelity has an impact on other functions including growth and longevity. In Aim 2, we will identify the molecular genetic basis for variation in developmental errors/fidelity in PCD and L/R organ handedness and other events. While the high-risk/high-gain aspect of the proposed studies make them appropriate for the R21 mechanism, important results relevant to stochasticity of PCD and dysregulation of L/R organ asymmetry will be obtained regardless of the generality of fidelity-controlling mechanisms. The proposed studies promise to yield new information regarding regulatory mechanisms underlying birth defects and dysregulation of cell proliferation, including in cancer. In addition, uncovering mechanisms that lead to inappropriate, stochastic cell death may provide important insights into sporadic cell death in neurodegenerative diseases.

 描述（由申请人提供）：发育中的胚胎面临着大量的平行和顺序的决定，每个决定都面临着波动的环境和分子“噪音”，因此充满了一定的错误率。虽然纠正决策错误的质量控制系统必须普遍存在，对人类发展至关重要，但人们对它们几乎一无所知。驱动拟议的研究的假设是，存在质量控制系统，在开发过程中，确保高保真的结果，这样的系统可能会在不同的发展过程中发挥作用。我们将利用C. elegans研究调节发育保真度的机制。我们发现C.雄性线虫在尾鳍感觉结构形成过程中程序性细胞死亡（PCD）的激活和主要器官的左右（L/R）方向上显示出频繁的“错误”，并且这些错误的倾向在不同的野生分离株（同种型）之间差异很大。在这两个过程中具有高错误率的同种型（“低保真度”菌株）在其他过程中也显示出高变异，包括生殖系干细胞增殖和L1幼虫长度。相比之下，在前一个性状中具有低错误率（“高保真度”）的菌株在后一个性状中也显示出低方差。我们建议揭示随机PCD和错误的L/R手性的分子遗传基础，并调查是否不同的发展过程的保真度可能会受到共同的机制，通过两个目标。在目的1中，我们将调查保真度的变化是否是完全独立的或显着的共变跨越几个发展过程中的错误分析不同的发展过程中的97个同种型和重组自交系（RILs）来自“高”和“低保真度”同种型。我们将评估忠诚度是否对其他功能（包括生长和寿命）产生影响。在目标2中，我们将确定PCD和L/R器官利手和其他事件中发育错误/保真度变化的分子遗传基础。虽然高风险/高收益方面的建议的研究，使他们适合的R21机制，重要的结果相关的随机性的PCD和失调的L/R器官不对称性将获得无论生育控制机制的一般性。拟议中的研究有望产生关于出生缺陷和细胞增殖失调（包括癌症）背后的调控机制的新信息。此外，揭示机制，导致不适当的，随机的细胞死亡可能会提供重要的见解零星细胞死亡的神经退行性疾病。