Mechano-enzymatic cleavage of transthyretin in systemic amyloidosis: elucidation of mechanism and characterization of putative proteases

系统性淀粉样变性中转甲状腺素蛋白的机械酶裂解：阐明推定蛋白酶的机制和表征

• 批准号: MR/R016984/1
• 负责人: Vittorio Bellotti
• 金额: $ 52.19万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR016984%2F1
• 关键词: Mechano; enzymatic; cleavage; transthyretin; systemic

Amyloidosis is a group of rare, serious and usually fatal diseases, responsible for the deaths of about one per thousand people who die in developed countries. It is caused by deposition of abnormal, insoluble, protein fibres, known as amyloid, in the tissues and organs of the body including the heart, kidneys, bowel, nerves and skin. Amyloid is derived by transformation of the body's own normal proteins into a mass of solid amyloid fibres; this leads to disruption and eventually organ failure. Transthyretin (TTR) is one of these "amyloidogenic" proteins and can result in a familial (hereditary) form of the disease. TTR amyloid also occurs in the elderly, making TTR amyloidosis a disease of ageing with profound clinical and socio-economic consequences. We have recently discovered that plasmin, an important enzyme in the normal blood clotting process is important in the development of TTR amyloid fibrils. Under conditions which are found in the heart, this enzyme breaks down TTR and leads directly to the formation of amyloid fibres. We will look at all the steps in the formation of TTR amyloid, particularly looking at the effects of both currently available and newly developed drugs. We will examine the relationship between the physiological (normal) pathway of blood clotting and the pathogenic (abnormal) pathway of TTR fibrillogenesis. Plasmin not only breaks down blood clots but may also activate the formation of amyloid by our newly discovered route. Our new understanding of how these two natural systems interact will allow us to evaluate the effect of anti-plasmin drugs on TTR amyloid formation. We believe that this work will improve our understanding of the causes of TTR amyloidosis, but will also be of major interest to the mechanism of other protein misfolding diseases.

淀粉样变性是一组罕见、严重且通常致命的疾病，在发达国家，每千人中就有一人死于淀粉样变性。它是由异常的、不溶的蛋白质纤维（即淀粉样蛋白）沉积在身体的组织和器官（包括心脏、肾脏、肠道、神经和皮肤）引起的。淀粉样蛋白是由人体自身的正常蛋白质转化为大量固体淀粉样纤维而产生的；这将导致破坏并最终导致器官衰竭。转甲状腺素（TTR）是这些“淀粉样蛋白”之一，可导致家族（遗传）形式的疾病。TTR淀粉样蛋白也发生在老年人中，使TTR淀粉样病成为一种具有深刻临床和社会经济后果的衰老疾病。我们最近发现，正常凝血过程中的一种重要酶——纤溶酶在TTR淀粉样原纤维的形成中起重要作用。在心脏中发现的情况下，这种酶会分解TTR并直接导致淀粉样蛋白纤维的形成。我们将研究TTR淀粉样蛋白形成的所有步骤，特别是目前可用的和新开发的药物的影响。我们将探讨血凝的生理（正常）途径与TTR纤维形成的致病（异常）途径之间的关系。纤溶蛋白不仅可以分解血凝块，还可以通过我们新发现的途径激活淀粉样蛋白的形成。我们对这两个自然系统如何相互作用的新认识将使我们能够评估抗纤溶酶药物对TTR淀粉样蛋白形成的影响。我们相信这项工作将提高我们对TTR淀粉样变病因的理解，但也将对其他蛋白质错误折叠疾病的机制产生重大兴趣。

项目成果

Plasminogen activation triggers transthyretin amyloidogenesis in vitro.

• DOI: 10.1074/jbc.ra118.003990
• 发表时间: 2018-09-14
• 期刊: The Journal of biological chemistry
• 作者: Mangione PP;Verona G;Corazza A;Marcoux J;Canetti D;Giorgetti S;Raimondi S;Stoppini M;Esposito M;Relini A;Canale C;Valli M;Marchese L;Faravelli G;Obici L;Hawkins PN;Taylor GW;Gillmore JD;Pepys MB;Bellotti V
• 通讯作者: Bellotti V

Calcium Binds to Transthyretin with Low Affinity.

• DOI: 10.3390/biom12081066
• 发表时间: 2022-08-02
• 期刊: Biomolecules
• 影响因子: 5.5

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms.

• DOI: 10.3389/fmolb.2022.830006
• 发表时间: 2022
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Faravelli G;Mondani V;Mangione PP;Raimondi S;Marchese L;Lavatelli F;Stoppini M;Corazza A;Canetti D;Verona G;Obici L;Taylor GW;Gillmore JD;Giorgetti S;Bellotti V
• 通讯作者: Bellotti V

Basic and applied science at the time of COVID-19.

COVID-19 时期的基础科学和应用科学。

• DOI: 10.1002/1873-3468.13927
• 发表时间: 2020
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Governing Council Of The Italian Society Of Biochemistry;Molecular Biology
• 通讯作者: Molecular Biology

A Narrative Review of the Role of Transthyretin in Health and Disease.

• DOI: 10.1007/s40120-020-00217-0
• 发表时间: 2020-12
• 期刊: Neurology and therapy
• 影响因子: 3.7
• 作者: Liz MA;Coelho T;Bellotti V;Fernandez-Arias MI;Mallaina P;Obici L
• 通讯作者: Obici L