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The role of mitochondrial DNA mutations and inflammation in adult blindness caused by diabetic retinopathy

线粒体DNA突变和炎症在糖尿病视网膜病变引起的成人失明中的作用

基本信息

批准号：
2072399
负责人：
金额：
--
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2072399
关键词：
role mitochondrial DNA mutations inflammation

项目摘要

Diabetic retinopathy (DR) is a major cause of blindness in the working-age population for which there is no treatment. Mitochondria are cellular organelles and the site of energy production in the cell. Mitochondrial dysfunction is involved in the development of DR, we recently published the first human study showing that MtDNA changes can be detected in blood samples from DR patients and have found, using patient blood samples and animal/cell models, that diabetes can lead to elevated circulating MtDNA. As MtDNA resembles bacterial DNA it may elicit an inflammatory response via activation of the TLR9 pathway and activate inflammasomes. Recently we have discovered novel MtDNA mutations and deletions in DR patients. In the current project the student will (a) test the hypothesis that damaged MtDNA is causative of energy deficit in the retina and chronic inflammation in circulation (b) characterise the time course of mitochondrial changes associated with DR using in-vitro models and (c) Identify and test therapeutic and preventative strategies. For the rotation/year 1, the student will use human patient samples to define the incidence of MtDNA mutations in DR. These studies will be expanded further and ARPE 19 cells will be used to mimic the damage seen in the retina in hyperglycemic conditions in order to characterise the mitochondrial changes and then test a range of therapeutic strategies. The student will gain training in a range of cell biology and molecular biology techniques including tissue culture, DNA/RNA work, real time quantitative PCR, functional assays and bioenergetics.

糖尿病视网膜病变(DR)是劳动年龄人口失明的主要原因，目前尚无治疗方法。线粒体是细胞器，也是细胞中产生能量的场所。线粒体功能障碍参与了糖尿病视网膜病变的发生，我们最近发表的第一项人类研究表明，可以在糖尿病患者的血液样本中检测到线粒体DNA的变化，并通过使用患者血液样本和动物/细胞模型发现，糖尿病可以导致循环中线粒体DNA的升高。由于mtDNA类似于细菌DNA，它可能通过激活TLR9途径而引发炎症反应，并激活炎症体。最近，我们在DR患者中发现了新的线粒体DNA突变和缺失。在目前的项目中，学生将(A)测试mtDNA受损是视网膜能量不足和循环中慢性炎症的原因的假设，(B)使用体外模型描述与DR相关的线粒体变化的时间过程，以及(C)确定和测试治疗和预防策略。对于轮换/第一年，学生将使用人类患者样本来定义DR中mtDNA突变的发生率。这些研究将进一步扩大，ARPE 19细胞将被用于模拟高血糖条件下视网膜的损伤，以表征线粒体的变化，然后测试一系列治疗策略。学生将接受一系列细胞生物学和分子生物学技术方面的培训，包括组织培养、DNA/RNA工作、实时定量聚合酶链式反应、功能分析和生物能量学。