Complete genomic DNA sequence of the sooty mangabey MHC

乌白眉猴 MHC 的完整基因组 DNA 序列

基本信息

批准号：
8018373
负责人：
DANIEL E. GERAGHTY
金额：
$ 63.54万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018373
关键词：
Acquired Immunodeficiency Syndrome Africa African Animal Model Antigens Basic Science Benign Biological Cercocebus atys Cercopithecus aethiops Cercopithecus pygerythrus Chronic Clinical Research Communities Complex DNA Sequence Data Disease Doctor of Philosophy Fred Hutchinson Cancer Research Center Future Gene Expression Genes Genetic Genetic Polymorphism Genetic screening method Genome Genomic Library Genomics HIV HIV-1 HIV-2 Health Human Human Genome Project Immune Response Genes Immune response Immunologic Deficiency Syndromes Individual Infection Laboratories Location Macaca Macaca mulatta Major Histocompatibility Complex Methods Phase Phenotype Population Principal Investigator Property Research Resources SIV Screening procedure Seroprevalences Structure Technology Time Universities Vaccine Design Virus Diseases Washington comparative cost nonhuman primate receptor research study transmission process

项目摘要

DESCRIPTION (provided by applicant): Simian immunodeficiency viruses (SIV) naturally infect a variety of nonhuman primates of African origin. SIV seroprevalence is particulariy high in some troops of sooty mangabeys (Cercocebus atys atys). While SIV share many structural and biological properties with human immunodeficiency viruses (HIV), they rarely induce AIDS in their natural hosts. The causative factors that underlie the ability of the same SIV isolate to induce disease in one species and a chronic but benign infection in another species are host genetic factors that have to a large extent been little characterized. A central component of these genetic factors is the Major Histocompatibiltiy Complex (MHC), within which the MHC class I and II antigen-presenting genes reside, alongside a large number of other genes, including some that control MHC-I and -II expression and genes that are in other ways involved in the host immune response. As the human genome project has shown many times over, the establishment of framework genomic DNA sequences can provide fundamental support for, and extension of, a plethora of basic and clinical research studies that are now advancing human health. However, as the human genome project has also shown, establishing framework DNA sequences for regions of the genome harboring immune response genes, including notably the MHC region, is difficult and has largely been ignored by those efforts. We propose to combine commercially available advancements in sequencing technology with methods proven to produce high quality genomic sequence to yield a completed phased genomic DNA sequence of the sooty mangabey MHC as a resource for future studies, including comparative analysis with the rhesus macaque MHC sequence, which we previously completed. Such a resource will provide a direction for functional testing of genetic factors that relate to long- term nonprogression of SIV infection in rhesus macaques, and then to the same phenotype for HIV-1 infection in humans. The identification of causative host genetic factors that control HIV-1 infection in humans would have important implications for disease treatment as well as for vaccine design. To accomplish these objectives we propose to carry out the following specific aims: (1) To derive complete and high quality genomic sequences of the major histocompatibility complex (MHC) and killer Ig-like receptor (KIR) regions from the sooty mangabey. (2) To annotate and make available the derived sequences with an emphasis towards relevance to the SIV research community. PUBLIC HEALTH RELEVANCE (provided by applicant): Simian immunodeficiency viruses (SIV) naturally infect a variety of nonhuman primates and share many structural and biological properties with human immunodeficiency viruses (HIV), but rarely induce AIDS in their natural hosts. We propose to produce a completed phased genomic DNA sequence of the sooty mangabey major histocompatibility complex (MHC) as a resource for future studies using animal models of human HIV-1 infection. This resource will contribute to identifying causative host genetic factors controlling HIV-1 infection in humans, providing direction for disease treatment as well as for vaccine design.

描述（由申请人提供）：猿猴免疫缺陷病毒（SIV）自然感染多种非洲起源的非人类灵长类动物。在一些乌白眉猴（Cercocebus atys atys）群体中，SIV 血清流行率特别高。虽然 SIV 与人类免疫缺陷病毒 (HIV) 具有许多相同的结构和生物学特性，但它们很少在自然宿主中诱发艾滋病。同一SIV分离株在一个物种中诱发疾病并在另一个物种中诱发慢性但良性感染的能力的致病因素是宿主遗传因素，但在很大程度上尚未得到表征。这些遗传因素的核心组成部分是主要组织相容性复合体 (MHC)，其中存在 MHC I 类和 II 类抗原呈递基因，以及大量其他基因，包括一些控制 MHC-I 和 -II 表达和以其他方式参与宿主免疫反应的基因。正如人类基因组计划多次表明的那样，框架基因组 DNA 序列的建立可以为目前正在促进人类健康的大量基础和临床研究提供基础支持和扩展。然而，正如人类基因组计划也表明的那样，为含有免疫反应基因的基因组区域（尤其是 MHC 区域）建立框架 DNA 序列是很困难的，并且在很大程度上被这些努力所忽视。我们建议将商业上可用的测序技术进步与经证明可产生高质量基因组序列的方法相结合，以产生乌白眉猴 MHC 的完整定相基因组 DNA 序列，作为未来研究的资源，包括与恒河猴 MHC 序列的比较分析，我们之前完成了。这样的资源将为与恒河猴 SIV 感染长期不进展相关的遗传因素的功能测试提供方向，然后为人类 HIV-1 感染的相同表型进行功能测试。识别控制人类 HIV-1 感染的致病宿主遗传因素将对疾病治疗和疫苗设计产生重要影响。为了实现这些目标，我们建议实现以下具体目标：（1）从乌白眉猴中获得主要组织相容性复合物（MHC）和杀伤性Ig样受体（KIR）区域的完整且高质量的基因组序列。 (2) 注释并提供衍生序列，重点是与 SIV 研究界的相关性。公共卫生相关性（由申请人提供）：猿猴免疫缺陷病毒（SIV）自然感染多种非人类灵长类动物，并与人类免疫缺陷病毒（HIV）共享许多结构和生物学特性，但很少在其自然宿主中诱发艾滋病。我们建议生产乌白白眉主要组织相容性复合体（MHC）的完整定相基因组DNA序列，作为未来使用人类HIV-1感染动物模型进行研究的资源。该资源将有助于确定控制人类 HIV-1 感染的致病宿主遗传因素，为疾病治疗和疫苗设计提供指导。