Targeting immunomodulation following cardiac injury

在英国，心血管疾病造成的死亡人数占所有死亡人数的四分之一以上（每年约有170，000人死亡-平均每天460人死亡，即每三分钟一人死亡）。其中，冠心病是最常见的，也是心脏病发作的主要原因。心脏病发作表现为肌肉细胞的大量死亡，超过约10亿，约占总心肌损失的25%。没有办法来取代这些失去的细胞，因此，通过形成非收缩性疤痕来修补损伤，以防止心脏壁破裂。这反过来又增加了存活肌肉的负担，导致细胞大小增加、壁变薄、腔室扩张，最终进展为心力衰竭。目前，英国约有90万人患有心力衰竭;器官移植是目前唯一的长期解决方案，但由于免疫排斥和需求不断超过供体心脏的可用性而变得复杂。替代的再生方法集中在替代从各种来源（骨髓、脂肪组织和骨骼肌）产生的丢失的细胞，然而，这些方法在很大程度上都失败了，临床试验结果令人失望。其中一个原因是，由于免疫细胞的入侵，受损心脏的局部环境变得高度发炎和瘢痕化，这反过来又导致进一步的细胞死亡和无法支持新细胞整合到存活的组织中。在身体的其他地方，免疫细胞在受伤后被淋巴管清除到引流淋巴结（例如。皮肤切除损伤后）。我们最近发现，心脏的血管对小鼠的损伤做出了发芽反应，并进一步确定了这些扩张的血管具有清除免疫细胞的功能，当通过生长因子治疗增加免疫细胞时，可以改善心脏病发作后的结果。在这项提案中，我们试图确定心脏组织生长的定时刺激是否可以定义损伤后干预的最佳窗口，以及哪些类型的免疫细胞最好保留在心脏中，而不是清除淋巴结，以优化心脏病发作后的心脏修复和功能。将精确定义的免疫细胞的定时清除与结果相关联，将使我们能够将功能独特地归因于免疫细胞的不同子集，作为重要的见解。我们还将模拟人类淋巴管及其与免疫细胞的相互作用，并筛选这些模型中可能激活免疫细胞的药物化合物。这将代表针对当地环境的药物发现管道的第一阶段，以实现细胞再生和组织恢复，作为治疗心脏病发作患者的联合疗法的一部分。

Cardiovascular diseases cause more than a quarter of all deaths in the UK, (approximately 170,000 deaths each year - an average of 460 deaths each day or one every three minutes). Of these, coronary heart disease is the most common and is the leading cause of heart attack. Heart attack manifests as massive death of muscle cells, upwards of around one billion, accounting for around 25% loss of the total heart muscle. There is no means to replace these lost cells and consequently the injury is patched-up by the formation of a non-contractile, scar to prevent rupture of the wall of the heart. This, in turn, increases the burden on survived muscle and results in increased cell size, wall thinning, dilation of the chambers and ultimately progression to heart failure. Currently there are around 900,000 people living in the UK with heart failure; organ transplantation is the only current long-term solution, but is complicated by immune rejection and the fact that demand continually outstrips the availability of donor hearts. Alternative regenerative approaches have centred on the replacement of lost cells generated from a variety of sources (bone marrow, fat tissue and skeletal muscle), however, these have largely failed, with disappointing clinical trial results. One reason for this is that the local environment of the injured heart becomes highly inflamed and scarred due to the invasion of immune cells which in turn leads to further cell death and failure to support the integration of new cells into survived tissue. Elsewhere in the body immune cells are cleared to draining lymph nodes by lymphatic vessels after injury (for eg. following skin excision injury). We recently discovered that the lymphatics of the heart respond to injury in mice by sprouting and further identified that these expanding vessels function to clear immune cells which, when increased by growth factor treatment, improved the outcome after a heart attack. In this proposal, we seek to determine whether timed stimulation of the growth of cardiac lymphatics can define the optimal window for intervention after injury and which types of immune cells are best retained in the heart versus cleared lymph nodes to optimise heart repair and function after a heart attack. Correlating timed clearance of precisely defined immune cells with outcome, will enable us to uniquely attribute function to different subsets of immune cells as an important insight. We will also model human lymphatic vessels and their interactions with immune cells and screen these models for drug compounds which might activate the lymphatics. This will represent the first stage of a drug-discovery pipeline targeting the local environment, to enable cell repopulation and tissue restoration, as part of a combined therapy to treat heart attack patients.