Reactive (AA)Amyloidosis

反应性 (AA) 淀粉样变性

基本信息

  • 批准号:
    8250821
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 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:
    2011-01-01 至 2014-12-31
  • 项目状态:
    已结题

项目摘要

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)是由蛋白原纤维的细胞外沉积引起的,其破坏正常器官功能,通常导致死于肾、肝或心力衰竭。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、局限性肠炎等(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),以及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)、和高免疫球蛋白D综合征。它也是慢性感染性疾病的致命并发症,如截瘫或四肢瘫痪患者的骨髓炎。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理解是,SAA,一种在慢性炎症期间过量产生的104个氨基酸残基的单一多肽,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。这些原纤维沉积然后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取得了相当大的进展,但尚未开发出针对这种疾病的特异性治疗方法。在患有慢性炎性疾病的AA患者中,用减少炎症的药剂治疗已经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,炎症标志物(包括血清淀粉样蛋白A)的减少可能会预防或减缓AA淀粉样变性的进展;然而,许多患者对抗炎药物(包括免疫抑制剂和抗TNF生物制剂)没有完全反应。这是一组发生淀粉样变性的慢性病患者。虽然控制炎症可以预防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开发特定的治疗策略,以改变AA淀粉样变性的进展。这将在两条研究线中进行探索:目的1)使用AA淀粉样纤维形成的细胞培养模型来确定抗TNF剂可以抑制AA淀粉样沉积的机制。传闻报道表明,抗TNF药物可能以不仅仅是抑制炎症反应的能力以外的方式抑制AA淀粉样蛋白的进展。目的2)利用AA淀粉样变性小鼠模型,验证特异性反义寡核苷酸(阿索)减少SAA在肝脏的合成,通过限制AA原纤维前体的可用性来减少SAA并阻止淀粉样原纤维形成的进展的假设。这些目标的成功完成将为开发治疗这种致命疾病的特定疗法提供基础。 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、肉芽肿性肠病和感染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。退伍军人截瘫往往有慢性感染,如骨髓炎,因此,有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衰竭,因此需要进行慢性透析,这显著增加了患有这种进行性致命疾病的患者的医疗保健费用。退伍军人人群中年龄相关性淀粉样变性的患病率也有所增加,包括免疫球蛋白淀粉样蛋白、阿尔茨海默病和老年性心脏淀粉样变性。了解反应性淀粉样变性的发病机制可能不仅揭示了治疗AA淀粉样变性的途径,而且还揭示了退伍军人群体中其他形式的淀粉样变性的途径。

项目成果

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MERRILL D BENSON其他文献

MERRILL D BENSON的其他文献

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{{ truncateString('MERRILL D BENSON', 18)}}的其他基金

Pathogenesis and Treatment of AA Amyloidosis
AA型淀粉样变性的发病机制和治疗
  • 批准号:
    10292421
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
XIV International Symposium on Amliodosis
第十四届淀粉样变性国际研讨会
  • 批准号:
    8720185
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Reactive (AA)Amyloidosis
反应性 (AA) 淀粉样变性
  • 批准号:
    8046549
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Reactive (AA)Amyloidosis
反应性 (AA) 淀粉样变性
  • 批准号:
    8392979
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Reactive (AA)Amyloidosis
反应性 (AA) 淀粉样变性
  • 批准号:
    8586875
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
CLINICAL STUDY OF PRESENTATION AND PROGNOSIS OF HUMAN AMYLOIDOSIS
人类淀粉样变性的表现和预后的临床研究
  • 批准号:
    7606362
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
CLINICAL STUDY OF PRESENTATION AND PROGNOSIS OF HUMAN AMYLOIDOSIS
人类淀粉样变性的表现和预后的临床研究
  • 批准号:
    7379040
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
CLINICAL STUDY OF PRESENTATION AND PROGNOSIS OF HUMAN AMYLOIDOSIS
人类淀粉样变性的表现和预后的临床研究
  • 批准号:
    7205731
  • 财政年份:
    2005
  • 资助金额:
    --
  • 项目类别:
Clinical Study of Presentation and Prognosis of Human Amyloidosis
人类淀粉样变性的表现和预后的临床研究
  • 批准号:
    7045117
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
CLINICAL STUDY OF PRESENTATION AND PROGNOSIS OF HUMAN AMYLOIDOSIS
人类淀粉样变性的表现和预后的临床研究
  • 批准号:
    6117739
  • 财政年份:
    1998
  • 资助金额:
    --
  • 项目类别:
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