Forward Genetic Analysis of Innate Immune Signaling

先天免疫信号的正向遗传分析

• 批准号: 8523783
• 负责人: BRUCE A BEUTLER
• 金额: $ 78.78万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8523783
• 关键词: Alleles; Alzheimer' s Disease; Antibodies; Archives; Area; Atherosclerosis; Biochemical; Biochemistry; Biomedical Research; C-Type Lectins; Cells; Chromosome Mapping; Coin; Collaborations; Collection; Communicable Diseases; Communities; Complement; Complex; DNA Sequence; Data; Defect; Detection; Development; Disease; Elements; Ethylnitrosourea; Event; Failure; Feedback; Fire - disasters; Genes; Genetic; Germ-Line Mutation; Grant; Host resistance; Hour; Human; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologic Receptors; Individual Differences; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Instruction; Interleukin-1; Laboratories; Learning; Ligands; Measures; Mediating; Medicine; Microbe; Modeling; Molecular; Mus; Mutagenesis; Mutation; Natural Immunity; Organism; Performance; Phenotype; Play; Predisposition; Process; Proteins; Repression; Resistance to infection; Resources; Role; Seeds; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Solid; Somatic Cell; System; T-Lymphocyte; Technology; Testing; Transgenes; Vaccines; Work; adaptive immunity; base; cell type; congenital immunodeficiency; empowered; exome sequencing; genetic analysis; human disease; immune activation; induced pluripotent stem cell; meetings; pathogen; programs; receptor; response; secretion process; segregation; sperm cell; success; tool; validation studies

Innate immune responses permit strong resistance to infection during the hours and days that follow inoculation of microbes. The innate immune system is "hard wired" in the sense that it depends upon germline-encoded receptors to recognize microbes, and signal transduction pathways to elicit the genetic and biochemical responses that restrict infection. Within our species, inter-individual differences in susceptibility to infection likely reflect differences in innate immune performance, based on differences in genetic mal<eup. Sometimes these differences are extreme (i.e., severe immunodeficiency disease may result from some mutations); sometimes the differences are rather subtle, or manifested only in susceptibility to a small collection of infectious organisms. It is imperative to know the full complement of genes that are necessary and sufficient for host resistance, however we measure it. An excellent start has been made, in that we now know many of the receptors that sense infection, and the ligands that activate these receptors. This proposal, tightly integrated with the other components of the U19 grant, extends a classical genetic approach, already used with great success to delineate the signaling pathways that comprise our innate immune system. It is empowered by recent advances in two areas: 1) DNA sequencing, which has completely transformed the process by which mutations are identified, and 2) IPS cell technology, which permits the recapture of mutations made in primary somatic cells to the germline for genetic mapping and extended study in the context of a complete organism. Here we describe how we will use ENU mutagenesis in the mouse to screen to near-saturation in pursuit of every molecular component of the innate immune system. As these components are discovered, we will operate in close collaboration with our colleagues at SBMI, ANU, Stanford, and TSRI to understand how each element "works" in the context of immune signaling, and to determine the effect of each mutation on adaptive immunity, and development of the immune system. We will also study the roles played by the corresponding genes in human immune cells. Closely tied to (and dependent on) the Genetics Core Laboratory, our program will create a valuable resource for the biomedical research community, in that functionally null alleles will be created at the majority of loci in mice and archived as sperm for quick accessibility. Moreover, we will donate all mutations that yield an immunological phenotype to the MMRRC for distribution.

先天免疫反应允许在随后的几个小时和几天内强烈抵抗感染 接种微生物。天生的免疫系统是“硬连线”的，因为它取决于 种系编码的受体以识别微生物，并信号转导途径引起遗传 以及限制感染的生化反应。在我们的物种中，个人间差异 感染的敏感性可能反映了先天免疫表现的差异，基于差异 遗传性<eup。有时这些差异是极端的（即，严重的免疫缺陷疾病可能 由于某些突变而产生的）；有时，差异相当微妙，或仅在易感性中表现出来 少量的传染性生物。必须知道完全补充的基因 对于宿主阻力的必要且足够，但是我们测量它。在 我们现在知道许多感染感染的受体以及激活这些受体的配体。 该提案与U19赠款的其他组成部分紧密整合，扩展了经典的遗传 方法，已经成功地用于描述构成我们先天的信号传导途径 免疫系统。最近在两个领域的进步赋予了它：1）DNA测序 完全改变了发现突变的过程，以及2）IPS细胞技术， 允许重新捕获原代体细胞中的突变，以恢复生殖线的遗传映射和 在完整生物体的背景下进行扩展研究。在这里，我们描述了如何使用ENU诱变 在鼠标中筛选到近饱和，以追求先天免疫的每个分子成分 系统。当发现这些组件时，我们将与我们的同事密切合作 SBMI，ANU，Stanford和TSRI了解每个元素在免疫的背景下如何“起作用” 信号传导，并确定每个突变对自适应免疫的影响，并发展 免疫系统。我们还将研究相应基因在人免疫细胞中扮演的作用。 与遗传学核心实验室密切相关（并依赖于），我们的计划将创建一个有价值的 生物医学研究界的资源，在该功能无效的等位基因中，将在大多数人中创建 小鼠的基因座，并存档为精子，以便快速访问。而且，我们将捐赠所有突变 向MMRRC产生免疫表型以进行分布。