Analysis of the pathological effects of light chains and AL protein states

系统性AL淀粉样变性是由轻链或轻链片段与组织相互作用引起的高度异质性疾病。然而，对器官和组织特异性环境因素如何调节疾病的表现和进展仍知之甚少。为了阐明这些问题，我们将讨论以下目标：(i)评估心脏和肾脏的轻链病理。（ii）模型系统轻链状态的病理效应分析。（iii）将模型系统转化为人类病理学。本项目将检验组织和器官的生化和结构组成对AL淀粉样变性的表现、进展和预后的影响。我们将结合传统的组织学，免疫组织化学和图像分析工具以及高度先进的质谱成像技术来研究患者组织中轻链病理的机制。此外，我们将使用心脏和肾脏细胞进行细胞生物学研究，我们将测试在本研究单元中分析的特定蛋白质状态的病理相关性，以实现蛋白质结构特征与细胞效应之间的相关性。虽然这个项目的范围是了解心脏和肾脏的轻链病理机制，但组织内淀粉样蛋白监测的改进可能与新的诊断和治疗标准的发展有关。

Systemic AL amyloidosis is a highly heterogeneous disease arising from the interactions of light chains or light chain fragments with the tissue. However, it is still poorly understood how organ- and tissue- specific environmental factors modulate disease manifestation and progression. To shed some light on these issues we will address the following aims: (i) Assessment of the light chain pathology in the heart and kidney. (ii) Analysis of the pathological effects of light chain states in model systems. (iii) Translation of the model systems into human pathology. This pro-ject will test the hypotheses that the biochemical and structural composition of tissues and or-gans impacts on the manifestation, progression and prognosis of AL amyloidosis. We will combine conventional histological, immunohistochemical and image analysis tools with highly ad-vanced mass spectrometry imaging techniques to examine the mechanism of light chain pa-thology in patient tissues. In addition we will carry out cell biological studies using cardiac and renal cells, with which we will test the pathological relevance of the specific protein states analyzed in this research unit to enable correlations between protein structural features and cellular effects. Although the scope of this project is on understanding the mechanism of light chain pathology in the heart and kidney, improvements in the monitoring of amyloid inside the tissue may have relevance for the development of novel diagnostic and therapeutic standards.