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，蛋白质原纤维破坏了正常的器官功能，通常导致肾脏，肝或心脏衰竭死亡。这是许多慢性炎症性疾病的严重并发症，包括类风湿关节炎，强直性脊柱炎，区域肠炎（克罗恩病）以及继承的复发性疾病疾病，例如常染色体隐性隐性遗传性家族性地中海发烧（FMF），以及一组自身体现的受体综合群体综合综合征， Muckle-Wells综合征，家族性冷荨麻疹（FCA）和高免疫球蛋白D综合征。这也是截瘫患者或四肢瘫痪患者的慢性传染病（例如骨髓炎）的致命并发症。所有这些疾病，无论是获得的还是遗传的，都会引起复发性炎症，导致血清淀粉样蛋白A（SAA）家族的急性相蛋白表达升高。 SAA是血浆HDL的载脂蛋白，是淀粉样蛋白原纤维亚基AA的前体。当前对AA淀粉样变化的发病机理的理解是，SAA是一种在慢性炎症期间过量生产的104个氨基酸残基的单一多肽，是部分蛋白水解的，而氨基末端1-76残基骨料聚集以形成无溶的纤维纤维。然后，这些原纤维沉积会损害正常的组织功能并导致进行性器官衰竭。尽管在理解AA淀粉样蛋白形成涉及的致病机制方面取得了长足的进步，但尚未开发针对该疾病的具体疗法。在AA患有慢性炎症性疾病治疗以减少炎症的患者中，炎症已成为治疗原发性疾病的主要支出，即SAA血液水平降低会减少AA淀粉样蛋白沉积的形成。大量的临床证据表明，包括血清淀粉样蛋白A在内的炎症标志物的降低可能会预防或减缓AA淀粉样变性的进展。但是，许多患者对包括免疫抑制和抗TNF生物学剂在内的抗炎剂没有完全反应。这是一组慢性病患者，患有淀粉样变性。虽然控制炎症可能会阻止AA淀粉样变性的发展，但一旦该过程开始有效改变进展的方法。该提案的总体目的是开发特定的治疗策略来改变AA淀粉样变性的进展。这将在两条研究中进行探讨：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药物可以抑制AA淀粉样蛋白沉积的机制。轶事报告表明，抗TNF药物可以以其他方式抑制AA淀粉样蛋白的进展，而不仅仅是抑制炎症反应的能力。目的2）使用AA淀粉样变性的鼠模型测试以下假设：通过特定的反义寡核苷酸（ASO）减少SAA肝合成可以减少SAA，并通过限制AA纤维前体的可用性来减少SAA并停止淀粉样蛋白原纤维形成的进展。这些目标的成功完成将为开发特定的治疗治疗这种致命疾病提供基础。 公共卫生相关性： 在退伍军人人群中，包括类风湿关节炎，强直性脊柱炎，肉芽肿性肠病和传染病在内的慢性炎症性疾病在退伍军人人群中很常见。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。患有截瘫的退伍军人通常患有慢性感染，例如骨髓炎，因此，AA淀粉样变性的发生率增加。由于反应性淀粉样变性通常会导致肾衰竭，因此需要慢性透析，并显着增加这种进行性致命疾病患者的医疗保健成本。资深人群的患病率也增加了与年龄相关的淀粉样蛋白，包括免疫球蛋白淀粉样蛋白，阿尔茨海默氏病和老年心脏淀粉样变性。了解淀粉样变性的反应性形式的发病机理可能揭示了不仅治疗AA淀粉样变性的途径，而且还可以治疗退伍军人人群中其他形式的淀粉样变性。