TARGETING THE GRANULOMA MICROENVIRONMENT TO IMPROVE TUBERCULOSIS TREATMENT

 描述（由申请人提供）：针对肉芽肿微环境，以改善结核病治疗结核病（TB）是一种全球性的祸害，每年造成近200万人死亡。结核病感染的一个标志是肺肉芽肿--由于对结核杆菌（结核分枝杆菌）的免疫反应而产生的不溶解的致密细胞团块。我们已经发现TB肉芽肿与实体恶性肿瘤共有许多生理异常，包括缺氧和坏死区域，以及异常致密的细胞外基质（即，广泛纤维化）。我们还发现肉芽肿相关血管的结构和功能异常（PNAS 2015）。在肿瘤中，我们发现实体组织成分，细胞和基质，施加“固体应力”-一种物理力-可以压缩血管（Nature 2004; PNAS 2012）。正如我们在肿瘤中所见，纤维化结核肉芽肿有很高比例的血管塌陷，我们假设这是由于“固体应力”。血管塌陷可减少肉芽肿血液灌注，导致氧气和药物向受影响组织的输送效率低下。由此产生的缺氧和酸性条件导致免疫抑制环境，从而使免疫细胞极化为不能有效避免TB感染的表型。由于目前可用的治疗方案无法根除这种毁灭性疾病，显然迫切需要新的治疗策略。基于我们令人兴奋的初步发现，我们现在建议利用结核肉芽肿和癌性肿瘤之间惊人的相似性来指导靶向肉芽肿微环境的新型治疗方法。我们计划研究是否通过抗纤维化疗法减轻肉芽肿中的固体应力，正如我们在肿瘤中所做的那样（PNAS 2011; Nature Communications 2013），将改善血管灌注并增强氧合和药物递送，从而改善免疫反应和治疗结果。在目标1中，我们将建立肉芽肿基质水平、“固体应力”和血管塌陷之间的关系，并将研究抗纤维化药物治疗是否会重塑基质。在目的2中，我们将研究是否用抗纤维化药物治疗可以减轻肉芽肿中固体应力的不良作用。最后，在目标3中，我们将确定连续性抗纤维化治疗是否增强TB化疗的疗效。为了实现这些目标，我们的合作者，国家过敏和传染病研究所的克利夫顿巴里博士将在结核病的兔子模型中进行实验，他是结核病领域的领导者。此外，创新和强大的成像技术将被应用于提供前所未有的分子，细胞，结构和功能知识的障碍，治疗肉芽肿。因此，对于我的博士前研究，我计划运用我作为一名工程师的技能来确定“固体压力”在结核病进展中的作用，并探索克服结核病治疗障碍的策略，同时发展我在结核病，癌症生物学和转化研究方面的技能和知识。

 DESCRIPTION (provided by applicant): Targeting the Granuloma Microenvironment to Improve Tuberculosis Treatment Tuberculosis (TB) is a global scourge that is responsible for nearly 2 million deaths annually. A hallmark of TB infection is pulmonary granulomas - non-resolving, dense cellular masses that result from the immune response to the TB bacillus, Mycobacterium tuberculosis. We have found that TB granulomas share many physiological abnormalities with solid malignant tumors, including regions of hypoxia and necrosis, and abnormally dense extracellular matrix (i.e., extensive fibrosis). We have also discovered that granuloma- associated blood vessels are abnormal in structure and function (PNAS 2015). In tumors, we have found that the solid tissue components, cells and matrix, exert "solid stress" - a type of physical force - that can compress blood vessels (Nature 2004; PNAS 2012). Just as we have seen in tumors, fibrotic TB granulomas have high proportions of collapsed blood vessels, which we hypothesize is due to "solid stress". Vessel collapse can reduce granuloma blood perfusion, causing inefficient delivery of oxygen and drugs to the affected tissue. The resulting hypoxic and acidic conditions cause an immunosuppressive environment, thus polarizing the immune cells to a phenotype that is unable to effectively stave off the TB infection. Due to the inability of currently available treatment regimens to eradicate this devastating disease, it is clear that new treatment strategies are urgently needed. Building on our exciting preliminary findings, we now propose to exploit the striking similarities between TB granulomas and cancerous tumors to guide novel therapeutic approaches that target the granuloma microenvironment. We plan to investigate whether alleviating solid stress in granulomas via anti-fibrotic therapies, as we have done successfully in tumors (PNAS 2011; Nature Communications 2013), will improve vascular perfusion and enhance oxygenation and drug delivery, resulting in improvedimmune response and treatment outcome. In Aim 1, we will establish the relationship between granuloma matrix levels, "solid stress", and vessel collapse, and will investigate whether treating with an anti-fibrotic agent will remodel the matrix. In Aim 2 we will investigate whether treating with an anti-fibrotic agentsalleviates the adverse effects of solid stress in granulomas. Finally, in Aim 3, we will determine whether adjunctive anti- fibrotic therapy enhances the therapeutic efficacy of TB chemotherapy. To realize these aims, experiments will be carried out in a rabbit model of TB by our Collaborator, Dr. Clifton Barry at the National Institute of Allergy and Infectious Diseases, a leader in the field of TB. Furthermore innovative and robust imaging techniques will be applied to provide unprecedented molecular, cellular, structural, and functional knowledge of barriers to treatment in granulomas. Thus, for my predoctoral studies, I plan to apply my skills as an engineer to determine the role of "solid stress" in TB progression and to explore strategies to overcome barriers to TB treatment, while developing my skills in and knowledge of TB, cancer biology, and translational research.