Role of abnormal collagen (I) homotrimer in cardiovascular ageing and disease

心血管疾病影响心脏和血管。它们是全球死亡的主要原因，占英国过早死亡的20%以上。这些疾病是英国南北健康不平等的主要原因，但也为发现新药提供了机会。作为自然衰老过程的一部分，血管系统会发生有害的变化。动脉硬化是衰老的标志，大动脉硬化是心血管疾病的重要危险因素。大动脉（如主动脉）中的病理和年龄相关变化由承载蛋白（如弹性蛋白和胶原蛋白）的变化控制。胶原蛋白是结缔组织的结构蛋白，为心肌、瓣膜和血管提供结构框架。已知胶原蛋白的遗传缺陷会导致心脏瓣膜问题和脆弱的血管，从而导致动脉瘤。随着年龄的增长，组织由于胶原蛋白的损失而经历与年龄相关的恶化，但也容易在可能出现问题的特定位置积累胶原蛋白。I型胶原蛋白的异常形式在遗传上与年龄相关的人类心血管疾病有关，并且有证据表明这种异常的有害胶原蛋白会随着衰老加剧局部胶原蛋白的积累。目的：该项目旨在确定异常胶原蛋白（I）如何影响心血管组织结构和生物力学，以及阐明其在衰老和患病组织中积累的程度和分布。目标1：I型胶原分子主要是来源于COL1A1和COL1A2基因的多肽基因产物的异源三聚体，而异常的I型胶原同源三聚体仅来源于COL1A1基因。COL1A2缺乏导致人类迟发性心脏瓣膜疾病，而在模式生物中已检测到早期左心室肥大。博士的第一个目标是确定I型胶原同源三聚体如何影响心血管组织的结构和生物力学。目标二：在人类疾病中，异常I型胶原同源三聚体似乎积聚在正常异源三聚体I型胶原的顶部，并且我们有证据表明异常I型胶原的合成随着衰老而增加。第二个目的是建立一种新的COL1A1过表达模型，并证实胶原（I）同源三聚体积累对心血管组织的影响。目的3：第三个目的是评估胶原（I）同源三聚体在心脏和主动脉组织老化中的分布和积累。为此，将产生并测试新的胶原蛋白（I）同源二聚体抗体，这对于将病理学与异常胶原蛋白积聚联系起来将是重要的。

Cardiovascular diseases affect the heart and blood vessels. They are the leading cause of mortality worldwide accounting for over 20% of premature deaths in the UK. The diseases are a major contributor to the UK's North-South health inequality but present opportunities for the discovery of new medicines. As part of the natural ageing process detrimental changes occur to the vascular system. Arterial stiffening is a hallmark of ageing and large artery stiffness is powerful risk factor for cardiovascular diseases. Pathological and age-related changes in large arteries such as the aorta are governed by changes in load-bearing proteins such as elastin and collagen. Collagen is a structural protein of connective tissue that provides the architectural framework for heart muscles, valves and blood vessels. Inherited defects in collagen are known to cause heart valve problems and fragile blood vessels that can lead to aneurysms. With ageing, tissues undergo age-related deterioration due to loss of collagen but also become predisposed to accumulate collagen at specific locations where it can become problematic. An abnormal form of type I collagen has been genetically linked to age-related human cardiovascular disease and there is evidence that this abnormal noxious collagen exacerbates localised collagen accumulation with ageing. Aims: This project aims to determine how abnormal collagen (I) affects cardiovascular tissue structure and biomechanics as well to elucidate the extent and distribution of its accumulation in ageing and diseased tissue. Objective 1: Type I collagen molecules are predominantly heterotrimers derived from the polypeptide gene products of the COL1A1 and COL1A2 genes, whereas abnormal type I collagen homotrimer is derived from the COL1A1 gene alone. COL1A2 deficiency results in late onset cardiac valve disease in humans whilst early left ventricular hypertrophy has been detected in model organisms. The first objective of the PhD is to determine how type I collagen homotrimer affects the structure and biomechanics of cardiovascular tissue. Objective 2: In human disease abnormal type I collagen homotrimer appears to accumulate on top of normal heterotrimeric type I collagen and we have evidence that synthesis of abnormal type I collagen is increased with ageing. The second objective is to develop a new model of COL1A1 over-expression and to characterise the effects of collagen (I) homotrimer accumulation on cardiovascular tissue. Objective 3: The third objective is to evaluate the distribution and accumulation of collagen (I) homotrimer in cardiac and aortic tissue ageing. To do this a new collagen (I) homotimer antibody will be generated and tested, which will be important to link pathology to abnormal collagen accumulation.