Role of abnormal collagen (I) homotrimer in cardiovascular ageing and disease
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Ageing and Chronic Disease
Abstract
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.
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.
Organisations
People |
ORCID iD |
| Vanja Pekovic-Vaughan (Primary Supervisor) | |
| Caroline Peters (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013840/1 | 01/10/2016 | 30/09/2025 | |||
| 1947223 | Studentship | MR/N013840/1 | 01/10/2017 | 25/07/2018 | Caroline Peters |