Reactive (AA)Amyloidosis

反应性 (AA) 淀粉样变性

• 批准号: 8046549
• 负责人: MERRILL D BENSON
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046549
• 关键词: Acute-Phase Proteins; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Fibrils; Amyloid deposition; Amyloidosis; Ankylosing spondylitis; Anti-Inflammatory Agents; Antisense Oligonucleotides; Apolipoproteins; Blood; Cardiac; Cell Culture Techniques; Cessation of life; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical; Communicable Diseases; Complication; Crohn' s disease; Deposition; Development; Dialysis procedure; Disease; Familial Mediterranean Fever; Familial amyloid nephropathy with urticaria and deafness; Family; Fever; Funding; Genetic; Granulomatous; Health Care Costs; Heart failure; Hepatic; High Density Lipoproteins; Hyperimmunoglobulinemia D; Immunoglobulins; Immunosuppressive Agents; In complete remission; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Intestines; Investigation; Kidney Failure; Knowledge; Lead; Liver Failure; Modeling; Mus; Normal tissue morphology; Organ; Organ failure; Osteomyelitis; Paraplegia; Pathogenesis; Patients; Plasma; Population; Prevalence; Process; Proteins; Proteolysis; Quadriplegia; Recurrence; Reporting; Research; Rheumatoid Arthritis; Secondary Amyloidosis; Serum amyloid A protein; Syndrome; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tumor Necrosis Factor-alpha; Urticaria; Veterans; age related; amyloid fibril formation; amyloid formation; base; extracellular; human TNF protein; human disease; inflammatory marker; polypeptide; prevent; protein structure; receptor

DESCRIPTION (provided by applicant): AA amyloidosis (reactive, secondary) is caused by the extracellular deposition of protein fibrils which disrupts normal organ function and usually leads to death from renal, hepatic or cardiac failure. It is a serious complication of many chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, regional enteritis (Crohn's disease), and inherited recurrent febrile diseases such as the autosomal recessive familial Mediterranean fever (FMF), and a group of autosomal dominant syndromes including TNF-alpha receptor associated periodic syndrome (TRAPS), Muckle-Wells syndrome, familial cold urticaria (FCAS), and hyper- immunoglobulin D syndrome. It is also a fatal complication of chronic infectious diseases such as osteomyelitis in patients with paraplegia or quadriplegia. All of these diseases, whether acquired or genetic, cause recurrent inflammation resulting in elevated expression of the acute phase proteins of the serum amyloid A (SAA) family. SAA, an apolipoprotein of plasma HDL, is the precursor of the amyloid fibril subunit AA. The current understanding of the pathogenesis of AA amyloidosis is that SAA, a single polypeptide of 104 amino acid residues, which is overproduced during chronic inflammation, is partially proteolyzed, and the amino-terminal 1- 76 residues aggregate to form insoluble fibrils. These fibril deposits then compromise normal tissue function and lead to progressive organ failure. While considerable progress has been made in understanding the pathogenic mechanisms involved in AA amyloid formation, no specific therapy for this disease has been developed. In AA patients with chronic inflammatory diseases treatment with agents to decrease inflammation have been the mainstay for treating the primary disease with the projection that reduction in SAA blood levels will curtail the formation of AA amyloid deposition. Considerable clinical evidence suggests that reduction in inflammatory markers, including serum amyloid A, may prevent or slow the progression of AA amyloidosis; however, many patients do not have complete response to anti-inflammatory agents including immunosuppressive and anti-TNF biologic agents. This is a group of chronic disease patients that develop amyloidosis. While control of inflammation may prevent the development of AA amyloidosis, once the process has started effective means of altering progression are not known. The overall objective of this proposal is to develop specific therapeutic strategies to alter progression of AA amyloidosis. This will be explored in two lines of investigation: Aim 1) Use a cell culture model of AA amyloid fibril formation to define the mechanisms by which anti-TNF agents may inhibit AA amyloid deposition. Anecdotal reports suggest that anti-TNF agents may inhibit AA amyloid progression in ways other than just their ability to suppress the inflammatory response. Aim 2) Use a murine model of AA amyloidosis to test the hypothesis that reduction of hepatic synthesis of SAA by specific antisense oligonucleotides (ASO) can reduce SAA and stop progression of amyloid fibril formation by limiting availability of AA fibril precursor. Successful completion of these aims will offer a basis for development of specific therapeutics to treat this fatal disease. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, granulomatous bowel disease, and infectious diseases are common in the Veteran population. Reactive (secondary) amyloidosis is a significant complication of these diseases and is usually fatal. Veterans with paraplegia often have chronic infections such as osteomyelitis and, therefore, have an increased incidence of AA amyloidosis. Since reactive amyloidosis very often leads to renal failure, chronic dialysis is required and significantly adds to health care costs in patients with this progressive fatal disease. The Veteran population also has an increase in prevalence of the age related amyloidoses including immunoglobulin amyloid, Alzheimer disease and senile cardiac amyloidosis. Understanding the pathogenesis of the reactive form of amyloidosis may reveal avenues for treatment of not only AA amyloidosis but also other forms of amyloidosis in the Veteran population.

描述（由申请人提供）： AA 淀粉样变性（反应性、继发性）是由蛋白质原纤维的细胞外沉积引起的，它会破坏正常的器官功能，通常会导致因肾、肝或心力衰竭而死亡。它是许多慢性炎症性疾病的严重并发症，包括类风湿性关节炎、强直性脊柱炎、局部性肠炎（克罗恩病）和遗传性复发性发热性疾病，如常染色体隐性家族性地中海热（FMF）和一组常染色体显性综合征（包括 TNF） -α受体相关周期性综合征 (TRAPS)、Muckle-Wells 综合征、家族性寒冷性荨麻疹 (FCAS) 和过敏性荨麻疹免疫球蛋白D综合征。也是截瘫或四肢瘫痪患者骨髓炎等慢性传染病的致命并发症。所有这些疾病，无论是获得性的还是遗传性的，都会引起复发性炎症，导致血清淀粉样蛋白 A (SAA) 家族的急性期蛋白表达升高。 SAA 是血浆 HDL 的载脂蛋白，是淀粉样原纤维亚基 AA 的前体。目前对AA淀粉样变性发病机制的认识是，SAA这种104个氨基酸残基的单一多肽，在慢性炎症过程中过量产生，被部分蛋白水解，氨基末端1-76个残基聚集形成不溶性原纤维。这些原纤维沉积物会损害正常组织功能并导致进行性器官衰竭。虽然在了解 AA 淀粉样蛋白形成的致病机制方面已经取得了相当大的进展，但尚未开发出针对这种疾病的具体疗法。在患有慢性炎症性疾病的 AA 患者中，使用减轻炎症的药物治疗已成为治疗原发性疾病的主要手段，预计 SAA 血液水平的降低将减少 AA 淀粉样蛋白沉积的形成。大量临床证据表明，减少炎症标志物（包括血清淀粉样蛋白 A）可以预防或减缓 AA 淀粉样变性的进展；然而，许多患者对包括免疫抑制剂和抗 TNF 生物制剂在内的抗炎药物没有完全反应。这是一群患有淀粉样变性的慢性病患者。虽然控制炎症可能会阻止 AA 淀粉样变性的发展，但一旦该过程开始，改变进展的有效方法尚不清楚。该提案的总体目标是制定具体的治疗策略来改变 AA 淀粉样变性的进展。这将通过两个研究方向进行探索： 目标 1) 使用 AA 淀粉样蛋白原纤维形成的细胞培养模型来定义抗 TNF 药物抑制 AA 淀粉样蛋白沉积的机制。轶事报告表明，抗 TNF 药物除了能够抑制炎症反应之外，还可以通过其他方式抑制 AA 淀粉样蛋白的进展。目标 2) 使用 AA 淀粉样变性小鼠模型来检验以下假设：通过特定反义寡核苷酸 (ASO) 减少 SAA 的肝脏合成，可以通过限制 AA 原纤维前体的可用性来减少 SAA 并阻止淀粉样蛋白原纤维形成的进展。成功完成这些目标将为开发治疗这种致命疾病的特异性疗法奠定基础。 公共卫生相关性： 慢性炎症性疾病，包括类风湿性关节炎、强直性脊柱炎、肉芽肿性肠病和传染病，在退伍军人群体中很常见。反应性（继发性）淀粉样变性是这些疾病的重要并发症，通常是致命的。截瘫退伍军人经常患有骨髓炎等慢性感染，因此 AA 淀粉样变性的发病率增加。由于反应性淀粉样变性经常导致肾功能衰竭，因此需要长期透析，并且显着增加患有这种进行性致命疾病的患者的医疗费用。退伍军人群体中与年龄相关的淀粉样变性的患病率也有所增加，包括免疫球蛋白淀粉样变性、阿尔茨海默病和老年心脏淀粉样变性。了解反应性淀粉样变性的发病机制可能不仅可以揭示治疗 AA 型淀粉样变性的途径，还可以揭示退伍军人群体中其他形式淀粉样变性的治疗途径。