Single-cell and spatial mapping of human diabetic cardiomyopathy

在糖尿病患者中，在没有冠状动脉疾病、瓣膜疾病或常规心血管危险因素(如高血压和血脂异常)的情况下，存在心肌功能障碍，从而产生了糖尿病心肌病这一术语。糖尿病心肌病的特征是心肌纤维化、功能失调性重构，以及相关的舒张期和晚期收缩功能障碍。其潜在机制尚不清楚，也不存在特定的治疗方法。我们有一个独特的生物库，其中有140例移植的糖尿病心肌病患者的心肌样本，并将使用20例排斥供者心脏，20例缺血性心肌病和20例单基因心肌病样本作为参考。可通过原位心脏移植(HTX)和/或脑室辅助装置植入获得脑室组织。我们将利用高分辨率空间转录组(DBIT-SEQ，5微米)，结合SnRNA和SnATAC序列，以前所未有的分辨率绘制人类糖尿病心肌病变的图谱。我们将使用遗传变异(SNPs)对样本进行多路复用和多路分解，以增加产量和降低成本。我们将应用最先进的以及新的定制计算方法，最终目标是确定机制和治疗目标。

In patients with diabetes mellitus, the presence of myocardial dysfunction in the absence of coronary artery disease, valvular disease or conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the term diabetic cardiomyopathy. Diabetic cardiomyopathy is characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic and later systolic- dysfunction. The underlying mechanisms are unclear and specific therapies do not exist. We have access to a unique biobank with samples of ventricular myocardium of 140 transplanted diabetic cardiomyopathy patients and will utilize 20 rejected donor hearts, 20 ischemic cardiomyopathy and 20 monogenetic cardiomyopathy specimens as references. The ventricular tissue is available from orthotopic heart-transplantations (HTx) and/or ventricular assist device implantations. We will utilize high resolution spatial transcriptomics (DBIT-seq, 5µm) combined with snRNA and snATAC seq to map human diabetic cardiomyopathy at unprecedented resolution. We will multiplex specimen and demultiplex using genetic variability (SNPs) to increase throughput and decrease costs. We will apply state-of-the-art as well as novel bespoke computational methodologies with the ultimative goal to identify mechanisms and therapeutic targets.