TARGETING THE GRANULOMA MICROENVIRONMENT TO IMPROVE TUBERCULOSIS TREATMENT

 描述(申请人提供)：以肉芽肿微环境为目标改善结核病治疗结核病(TB)是一种全球祸害，每年导致近200万人死亡。结核病感染的一个特征是肺肉芽肿--对结核杆菌--结核分枝杆菌的免疫反应产生的不能溶解的致密细胞性肿块。我们发现，结核肉芽肿与实体恶性肿瘤有许多共同的生理异常，包括缺氧区和坏死区，以及异常致密的细胞外基质(即广泛的纤维化)。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，我们发现固体组织成分、细胞和基质施加“固体压力”--一种物理力量--可以压缩血管(自然2004；PNAS 2012)。就像我们在肿瘤中看到的那样，纤维性结核肉芽肿有很高比例的血管塌陷，我们推测这是由于“固体压力”造成的。血管塌陷会减少肉芽肿血液灌注量，导致氧气和药物不能有效地输送到受影响的组织。由此产生的低氧和酸性条件会导致免疫抑制环境，从而使免疫细胞两极分化为无法有效延缓结核病感染的表型。由于目前可用的治疗方案无法根除这种毁灭性的疾病，显然迫切需要新的治疗战略。基于我们令人兴奋的初步发现，我们现在建议利用结核病肉芽肿和癌症肿瘤之间的惊人相似之处来指导针对肉芽肿微环境的新的治疗方法。我们计划研究通过抗纤维化治疗缓解肉芽肿中的固体应激，就像我们在肿瘤中成功做到的那样(PNAS 2011；自然通讯2013)，是否将改善血管灌流，增强氧合和药物输送，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，并将调查使用抗纤维化药物治疗是否会重塑基质。在目标2中，我们将调查使用抗纤维化药物治疗是否减轻肉芽肿中固体应激的不良影响。最后，在目标3中，我们将确定辅助抗纤维化治疗是否提高了结核病化疗的疗效。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上进行实验，他是结核病领域的领先者。此外，创新和强大的成像技术将被应用于提供前所未有的关于肉芽肿治疗障碍的分子、细胞、结构和功能知识。因此，在我的博士前研究中，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.