Cardiac and Arteriolar Lesions in Fabry Disease and Dysautonomia

法布里病和自主神经功能障碍的心脏和小动脉病变

• 批准号: 10264851
• 负责人: S. Michael Mauer
• 金额: $ 16.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264851
• 关键词: Age; Alpha-galactosidase; Apoptosis; Autonomic Dysfunction; Biological Assay; Biopsy; Blood Pressure; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cardiovascular system; Cause of Death; Cell Fraction; Cells; Clinical; Clinical Trials; Clinical Trials Design; Collection; Complication; Development; Disease; Dose; Dysautonomias; EFRAC; Effectiveness; End stage renal failure; Enzymes; Event; Fabry Disease; Female; Fibrosis; Functional Imaging; Functional disorder; Future; Grant; Half-Life; Heart; Heart Rate; Heart failure; Histology; Hypertrophy; Kidney; Kidney Diseases; Kidney Failure; Lead; Lesion; Long-Term Effects; Lysosomal Storage Diseases; Natural History; Organ; Patients; Pilot Projects; Proteinuria; Rare Diseases; Renal function; Reproducibility; Research Personnel; Residual state; Resistance; Risk; Severities; Skin; Smooth Muscle Myocytes; Specimen; Stroke; Testing; Tissues; Treatment outcome; Vascular Smooth Muscle; Ventricular; age effect; blood pressure variability; cell type; clinical decision-making; enzyme replacement therapy; globotriaosylceramide; glomerulosclerosis; heart function; heart rate variability; improved; insight; interstitial; kidney biopsy; male; mortality; novel; novel strategies; podocyte; response; sex; standard care; therapy resistant; tool; treatment response

Abstract Fabry disease, an uncommon disease caused by deficiency of lysosomal enzyme α-galactosidase A, leads to intracellular accumulation of its substrates, mainly globotriaosylceramide (GL3), causing severe multi-organ complications. Enzyme replacement therapy (ERT) is the current standard treatment for patients with Fabry disease. However, some cells, including kidney podocytes (PC), cardiac myocytes (CM) and vascular smooth muscle cells (VSMC), are relatively resistant to ERT, this creating residual risks in a substantial proportion of ERT treated patients for serious complications, such as stroke, heart and renal failure. While cardiovascular complications are the most common, and renal complications the next most common, cause of death in Fabry disease, the pathophysiology of the lesions underlying these complications is poorly understood and requires further studies. Such studies need access to large number of patients and biopsies and detailed clinical information, these being common roadblocks in the study of rare diseases. The Lysosomal Disease Network (LDN) has created a unique opportunity of networking among the investigators studying such rare diseases. Using our extensive network of collaborators inside and outside of LDN as well as our own rich cardiac, renal, and skin biopsy collections, we are extremely well poised to study the natural history and ERT treatment outcomes of the key lesions of cardiovascular and renal complications of Fabry disease through novel morphometric approaches that we have developed. These validated specific and quantitative approaches will allow us to describe the relationships between these lesions and cardiac and renal function. We will also study skin arteriolar VSMC including in patients with concomitant renal biopsies in order to determine if a less invasive approach will provide vital organ information regarding these important cells in less accessible tissues. In addition, we will study the effect of ERT on GL3 clearance from cardiac myocytes and cardiac, renal and skin VSMC so as to determine factors influencing the effectiveness of ERT. These studies are highly likely to provide reproducible and sensitive structural endpoints for future Fabry disease clinical trials exploring new treatment approaches. In addition, we will assess tilt table variability of heart rate and blood pressure response, as well as electrocardiographic (ECG) markers of ventricular depolarization/repolarization in order to detect the presence and severity of dysautonomia in Fabry disease and, in pilot studies, to test whether these dysautonomia and ECG parameters can predict the development of cardiac events/dysfunction in Fabry patients. These unique cardiac and renal projects are highly likely to lead to new insights furthering our understanding of Fabry disease and to new clinical trial strategies.

抽象的 Fabry病是由溶酶体酶α-半乳糖苷酶A缺乏引起的一种罕见疾病，导致 其底物的细胞内积累，主要是球形三环酰胺（GL3），导致严重的多器官 并发症。酶替代疗法（ERT）是Fabry患者的当前标准疗法 疾病。但是，一些细胞，包括肾脏足细胞（PC），心肌细胞（CM）和血管光滑 肌肉细胞（VSMC）对ERT具有相对抗性，这种造成了很大一部分的残留风险 ERT治疗患者患有严重的并发症，例如中风，心脏和肾衰竭。而心血管 并发症是最常见的，肾脏并发症下一个最常见的是法布里的死亡原因 疾病，这些并发症基础病变的病理生理学知之甚少，需要 进一步的研究。这样的研究需要进入大量患者和活检以及详细的临床 信息，这些是罕见疾病研究中常见的障碍。溶酶体疾病网络 （LDN）在研究这种罕见疾病的研究人员中创造了独特的网络机会。 使用我们在LDN内外的广泛合作者以及我们自己的富裕心脏，肾脏， 和皮肤活检收集，我们非常有毒，可以研究自然史和ERT治疗 Fabry病的心血管和肾脏并发症的关键病变通过新颖 我们开发的形态计量方法。这些经过验证的特定和定量方法将 允许我们描述这些病变与心脏和肾功能之间的关系。我们还将学习 皮肤小动脉VSMC包括肾脏活检的患者，以确定是否较少 侵入性方法将在较不访问的时机中提供有关这些重要细胞的重要器官信息。 此外，我们将研究ERT对心肌和心脏，肾脏和心脏，肾脏和心脏的GL3间隙的影响 皮肤VSMC以确定因素会影响ERT的有效性。这些研究很可能 为未来的Fabry病临床试验提供可重现和敏感的结构终点 治疗方法。此外，我们将评估心率和血压的倾斜表变异性 反应以及心室去极化/复置的心电图（ECG）标记，以便 检测功能障碍在Fabry病中的存在和严重程度，并在试点研究中测试是否存在 功能障碍和心电图参数可以预测Fabry中心脏事件/功能障碍的发展 患者。这些独特的心脏和肾脏项目极有可能导致新的见解进一步推动我们的 了解法布里病和新的临床试验策略。