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）： 全身性狼疮红肿（SLE）是一种具有显着发病率和死亡率的多系统疾病，其生殖年份主要影响女性。遗传和环境因素在其发病机理中起着重要作用。尽管取得了重大进展，但免疫介导的肾小球肾炎（GN）仍然是终结肾衰竭的主要原因。 PI的实验室通过研究Murine Model NZM2328，将重点放在狼疮GN的遗传方面。这种具有竞争性更新的应用程序是继续PI的研究计划，以鉴定狼异染色体1和ADNZ2在1号染色体上识别抗核和相关自身抗体（AB）的产生（AB）的产生，并最终器官抵抗在nzm2328 luus for n Zm2328 luus plultifitiative in n luus plultifitiative in n luus plultifity for for for nzm232328 luus timitife for lantial for lantial。在Currrent赠款期间，产生并表征了两条信息的290-2和507-2。该分析得出的结论是，该区域已被缩小到1.34MB区域，该区域对进一步的分析非常有害。自身免疫性和最终器官损伤的分离是独一无二的，PI的实验室仍然是专注于最终器官抗损伤的基因的主要部位。一组具有互补技能的研究人员已经组装，以利用分子和细胞生物学和动物遗传学的最新技术来解决这一技术要求的研究项目。为了实现该计划的长期目标，提出了四个具体目的：具体目的1：生成和表征NZm.c57LC1重组型菌株LC1（1.34MB），其中包含Interross繁殖（NZM2328X507-2）F1 X（NZM2322322328X507-X507-X507-X507-X507-X507-X507-X507-X507-X）;具体目的2：确定来自NZM2328 BAC库中的一组连续重叠的基因组克隆（重叠群），该克隆涵盖了1.34 MB感兴趣的区域，并将这些重叠群测序以通过将序列与129和B6/C57L的序列进行比较，以定义该区域中的多态性。多态性还可以鉴定CGNZ1和ADAZ2的潜在候选基因。 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.结果将提供确定的证据，表明控制最终器官损伤的基因在狼疮性肾炎中起着重要作用，并且它们与增强自身免疫性的基因相互作用，从而导致各种临床表现。在基本水平上，结果可能会改变我们对自身免疫性疾病的发病机理的思考。此外，这些结果具有显着的临床意义，因为遗传因素可能使我们能够为狼疮肾炎量身定制个体治疗方案，以最大程度地提高治疗目标并最大程度地减少毒性副作用。 公共卫生相关性： 全身性红斑狼疮是一种影响许多器官的疾病。它会引起大量的痛苦和早期死亡。它主要影响女性的生殖年龄。遗传因素起着重要作用。尽管在研究方面取得了重大进展，但肾脏疾病仍然是终结阶段肾衰竭的主要原因，需要慢性透析或肾脏移植。该建议是寻求资金继续研究计划，以确定影响自身免疫性的遗传因素，并使肾脏对自身抗体和/或自动反应性淋巴细胞的损害具有抗性。该研究计划正在利用研究人员实验室中建立的独特小鼠模型。研究计划的结果可以很容易地转化为患者护理，因为可以用个别治疗肾脏疾病治疗各个患者，并在缓解中维持研究。这将大大降低发病率和死亡率，以便患者保持活跃和生产力。因此，研究计划应对公共卫生产生重大影响。