Cellular and Genetic Basis of Systemic Lupus

系统性狼疮的细胞和遗传基础

• 批准号: 8099636
• 负责人: Shu Man Fu
• 金额: $ 48.27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099636
• 关键词: Acute; Acute Glomerulonephritis; Adrenal Cortex Hormones; Adverse effects; Affect; African American; Age; Age-Months; Alleles; Animal Genetics; Antibody Formation; Antigen-Antibody Complex; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Backcrossings; Bone Marrow Transplantation; Breeding; Candidate Disease Gene; Cells; Cellular biology; Cessation of life; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 4; Chronic; Chronic Glomerulonephritis; Chronic Kidney Failure; Clinical; Complex; Congenic Strain; Data; Databases; Dendritic Cells; Development; Dialysis procedure; Disease; Disease remission; End stage renal failure; Environmental Risk Factor; Family; Female; Funding; Gene Family; Gene Transfer Techniques; Genes; Genetic; Genetic Polymorphism; Genomic Segment; Genomics; Glomerulonephritis; Goals; Grant; Histones; Human; Human Characteristics; Immune; Immune response; Immunosuppressive Agents; Incidence; Individual; Intervention; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Knock-out; Laboratories; Libraries; Link; Location; Lupus; Lupus Nephritis; Lymphocyte; Maps; Mediating; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Names; Natural Killer Cells; Nuclear; Nucleosomes; Organ; Partner in relationship; Pathogenesis; Patient Care; Patients; Phenotype; Play; Predisposition; Production; Proteinuria; Public Health; Recombinants; Regimen; Research; Research Personnel; Research Project Grants; Resistance; Role; Site; Study models; Susceptibility Gene; System; Systemic Lupus Erythematosus; T-Lymphocyte; Techniques; Technology; Therapeutic; Thinking; Time; Translating; anti-dsDNA antibodies; anti-dsDNA autoantibody; base; cohort; complement pathway; congenic; ds-DNA; interest; kidney cell; macrophage; male; man; monocyte; mortality; mouse model; podocyte; prevent; programs; prototype; public health relevance; rapid technique; reproductive; research study; skills; systemic autoimmune disease

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE), a multi-system disorder with significant morbidity and mortality affects predominantly females in their reproductive years. Genetic and environmental factors play significant roles in its pathogenesis. Despite significant progress, immune mediated glomerulonephritis (GN) remains a major cause of end stage renal failure. The PI's laboratory has been focused on the genetic aspect of lupus GN by studying the murine model NZM2328. This competitive renewal application is to continue the PI's research program to identify lupus susceptibility genes, Cgnz1 and Adnz2, on chromosome 1 that confer the production of antinuclear and related autoantibodies (Ab) and end organ resistance to the development of chronic glomerulonephritis (cGN) respectively in NZM2328, a much studied model for human proliferative lupus nephritis. During the currrent grant period, two informative congenic lines, 290-2 and 507-2 were generated and characterized. This analysis led to the conclusion that this region has been narrowed to a 1.34Mb area that is very much amendable to further analysis. The separation of autoimmunity and end organ damage is unique and the PI's laboratory remains the major site to focus on the genes which contribute to end organ resistance to damage. A team of investigators with complementary skills have been assembled to utilize up-to- date techniques in molecular and cell biology and animal genetics to resolve this technically demanding research project. To achieve the long term objective of this program, four specific aims are proposed: Specific Aim 1: To generate and to characterize the NZM.C57Lc1 recombinant congenic strain Lc1(1.34Mb) that contains the 1.34Mb of interest by intercross breeding (NZM2328X507-2)F1 X (NZM2328X507-2)F1; Specific Aim 2: To identify a set of contiguous overlapping genomic clones (contigs) from the NZM2328 BAC library, which cover the 1.34 Mb region of interest and to sequence these contigs to define polymorphisms in this region by comparing the sequences with those of 129 and B6/C57L available in the database. The polymorphisms may also identify potential candidate genes for Cgnz1 and Adaz2; Specific Aim 3: To determine the transcriptional profiles of the 45 genes within this region in intrinsic kidney cells and in immune cells including T and B cells, dendritic cells, monocytes and macrophages and NK cells to identify candidate genes responsible for kidney resistance to damage and for those for enhanced autoimmune response and Specific Aim 4: To validate susceptibility by gene knockin technology or allele transgenesis. The results will provide conclusive evidence that genes controlling end organ damage play an important role in lupus nephritis and that they interact with genes that enhance autoimmunity resulting in various clinical presentations. On the basic level, the results may alter our thinking on the pathogenesis of autoimmune disorders. In addition, these results have significant clinical implication in that genetic factors may allow us to tailor individual therapeutic regimens for lupus nephritis to maximize therapeutic goals and to minimize toxic side effects. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus is a disease affecting many organs. It causes a significant amount of suffering and early death. It affects predominantly females at their reproductive ages. Genetic factors play a significant role. Despite significant progress in research, renal disease remains a major cause of end stage renal failure that requires either chronic dialysis or renal transplantation. This proposal is to seek funding to continue a research program to identify genetic factors that affect autoimmunity and render the kidney resistant to damage by autoantibodies and/or autoreactive lymphocytes. The research program is taking advantage of the unique mouse models established in the investigators' laboratory. The results of the research program can be readily translated to patient care in that individual patients can be treated with individual regimens for their renal disease and to maintain them in remission. This will reduce the morbidity and mortality significantly so that patients can remain active and productive. Thus the research program should have significant impact on public health.

描述（由申请人提供）： 系统性红斑狼疮 (SLE) 是一种具有显着发病率和死亡率的多系统疾病，主要影响育龄女性。遗传和环境因素在其发病机制中起着重要作用。尽管取得了重大进展，免疫介导的肾小球肾炎（GN）仍然是终末期肾衰竭的主要原因。 PI 实验室通过研究小鼠模型 NZM2328 来重点研究狼疮肾炎的遗传方面。这项竞争性更新申请旨在继续 PI 的研究计划，以确定 1 号染色体上的狼疮易感基因 Cgnz1 和 Adnz2，这些基因分别赋予抗核和相关自身抗体 (Ab) 的产生以及对慢性肾小球肾炎 (cGN) 发展的终末器官抵抗力NZM2328 是一种经过深入研究的人类增殖性狼疮肾炎模型。在当前的资助期内，产生并鉴定了两个信息丰富的同源系 290-2 和 507-2。该分析得出的结论是，该区域已缩小到 1.34Mb 区域，非常适合进一步分析。自身免疫和终末器官损伤的分离是独一无二的，PI 实验室仍然是关注有助于终末器官抵抗损伤的基因的主要场所。一支由具有互补技能的研究人员组成的团队已经组建起来，利用分子和细胞生物学以及动物遗传学领域的最新技术来解决这个技术要求很高的研究项目。为了实现该计划的长期目标，提出了四个具体目标： 具体目标 1：通过杂交育种（NZM2328X507-）产生并鉴定包含 1.34Mb 目标的 NZM.C57Lc1 重组同源菌株 Lc1（1.34Mb）。 2)F1×(NZM2328X507-2)F1;具体目标 2：从 NZM2328 BAC 文库中鉴定一组连续的重叠基因组克隆（重叠群），覆盖 1.34 Mb 的感兴趣区域，并对这些重叠群进行测序，通过将序列与 129 和 129 的序列进行比较来定义该区域的多态性。 B6/C57L 在数据库中可用。多态性还可以鉴定 Cgnz1 和 Adaz2 的潜在候选基因；具体目标 3：确定该区域内 45 个基因在固有肾细胞和免疫细胞（包括 T 细胞和 B 细胞、树突细胞、单核细胞和巨噬细胞以及 NK 细胞）中的转录谱，以确定负责肾脏抵抗损伤和损伤的候选基因。对于那些增强自身免疫反应和具体目标 4：通过基因敲入技术或等位基因转基因验证敏感性。这些结果将提供确凿的证据，证明控制终末器官损伤的基因在狼疮性肾炎中发挥重要作用，并且它们与增强自身免疫的基因相互作用，从而导致各种临床表现。在基本层面上，这些结果可能会改变我们对自身免疫性疾病发病机制的思考。此外，这些结果具有重要的临床意义，因为遗传因素可能使我们能够针对狼疮肾炎制定个体化治疗方案，以最大限度地提高治疗目标并最大限度地减少毒副作用。 公共卫生相关性： 系统性红斑狼疮是一种影响许多器官的疾病。它会导致大量的痛苦和早逝。它主要影响育龄女性。遗传因素起着重要作用。尽管研究取得了重大进展，但肾脏疾病仍然是终末期肾衰竭的主要原因，需要长期透析或肾移植。该提案旨在寻求资金来继续一项研究计划，以确定影响自身免疫的遗传因素，并使肾脏抵抗自身抗体和/或自身反应性淋巴细胞的损伤。该研究计划利用了研究人员实验室建立的独特小鼠模型。该研究计划的结果可以很容易地转化为患者护理，因为可以针对个别患者的肾脏疾病采用单独的治疗方案进行治疗并维持其缓解。这将显着降低发病率和死亡率，使患者能够保持活跃和高效。因此，该研究计划应对公众健康产生重大影响。