Investigating Matrix Degradation Products in Tuberculosis

结核病是一种肺部感染，通过咳嗽传播。它继续在世界范围内引起疾病，每天造成4 000多人死亡，并且对用于治疗它的抗生素的耐药性正在逐渐增强。由于标准诊断和治疗在过去30年中基本保持不变，因此迫切需要新的创新方法来控制这种疾病。结核病对肺部造成非常广泛的损害，我们已经证明，这会将肺原纤维的小碎片释放到血液中。男性和女性结核病患者的肺破坏不同，在感染艾滋病毒的情况下发生结核病时也是如此。保罗·埃尔金顿教授的研究小组先前研究了感染释放的少量碎片，但由于肺是一个高度复杂的相互连接的原纤维网络，许多碎片将在结核病中产生。该项目将使用一种称为蛋白质组学的新型分析系统来测量全范围的片段，该系统可以识别单个样品中的所有蛋白质。然后，这些片段可用于开发检测方法，以识别咳嗽结核病患者并积极感染他人，也可用于监测新治疗方法的效果。我将分析作为其他研究的一部分而收集的样本，并包括用于比较的重要群体：男性和女性、未感染艾滋病毒和感染艾滋病毒的个人，以及有肺结核症状的其他呼吸道疾病患者。首先，我将使用一种高度敏感但耗时的测试系统来测量少量样本中的所有基质分解产物，并将活动性肺结核患者与健康对照者进行比较。接下来，我将对所有已识别的碎片进行详细的计算分析，以及它们在各组之间的差异。一旦确定了最有趣的片段，我将在更多的样本中使用快速、高通量的方法来测量这些片段，包括具有其他呼吸系统疾病的个体，这些疾病可以模拟结核病，以确定诊断潜力，作为排除结核病的测试。最后，我将研究这些片段在不同种族和不同结核病表现的患者身上的表现。这项研究将对结核病患者的肺基质降解产物进行首次系统调查，我将确定可用于开发新的诊断测试以打破感染循环的片段。该项目还将为我提供尖端医学研究方法的良好培训，可用于解决广泛的人类疾病。

Tuberculosis is a lung infection that spreads by people coughing. It continues to cause disease worldwide, killing over 4,000 people per day, and is becoming progressively more resistant to the antibiotics used to treat it. New innovative approaches to control the disease are urgently needed as standard diagnosis and treatment have remained largely unchanged for the last 30 years. Tuberculosis causes very extensive damage to the lungs and we have shown that this releases small fragments of lung fibrils into the bloodstream. Lung destruction differs between men and women with tuberculosis, and also when tuberculosis occurs in the context of HIV infection. Professor Paul Elkington's research group has previously studied a small number of the fragments released by infection, but as the lung is a highly complex network of interconnected fibrils many fragments will be produced in tuberculosis. This project will measure the full range of fragments using a new type of analytical system called proteomics that can identify all the proteins in a single sample. These fragments can then be used to develop tests to identify patients who are coughing tuberculosis and actively infecting others, and also to monitor the effect of new treatments.I will analyse samples that have been collected as part of other studies and include the important groups for comparison: men and women, HIV uninfected and HIV infected individuals, and patients with other respiratory conditions who have symptoms suggestive of tuberculosis. First, I will measure all the matrix breakdown products in a small number of samples using a highly sensitive but time-intensive testing system comparing patients with active tuberculosis with healthy controls. Next, I will perform detailed computational analysis of all the fragments identified and how they differ between the groups. Once the most interesting fragments are identified, I will measure these using rapid, high-throughput approaches in a much larger number of samples, including individuals with other respiratory conditions that can mimic tuberculosis to characterise the diagnostic potential as a test to exclude tuberculosis. Finally, I will study these fragments in patients of different ethnic origin and various manifestations of tuberculosis. This study will perform the first systematic investigation of lung matrix degradation products in tuberculosis and I will identify fragments that can be used to develop a new diagnostic test to break the cycle of infection. The project will also provide me with an excellent training in cutting edge medical research methods that can be used to address a wide range of human diseases.