Regulation of Cortisol by Mycobacterial Glycolipid TDM

描述（由申请人提供）：结核感染期间糖皮质激素调节的观察已为人所知多年，然而，糖皮质激素免疫调节与对分枝杆菌抗原的破坏性病理和肉芽肿反应之间的关系仍然知之甚少。事实上，全身和组织特异性皮质醇的相对量可能在结核病易感性中至关重要，因此在随后的病理学中起决定性作用。C57 BL/6小鼠在急性实验性感染强毒结核分枝杆菌期间，在肉芽肿反应开始期间血清皮质醇水平迅速下降。研究人员积极寻求模拟与结核病相关的免疫病理学的药物。一个这样的代理人;天然分枝杆菌糖脂海藻糖3，6 ′-二霉菌酸酯（TDM）作为疾病期间生物事件和肉芽肿反应的介质已被广泛研究。我们进一步确定了分枝杆菌TDM能够影响全身血清皮质醇水平。这是首次观察到全身性糖皮质激素对分枝杆菌糖脂的介导作用，值得进一步研究。 我们的初步研究结果表明，需要探讨皮质醇对初始事件的影响，涉及免疫调节和免疫病理学由于分枝杆菌糖脂TDM。因此，本申请的目的是检查在肺肉芽肿反应发展期间由分枝杆菌糖脂诱导的免疫反应与血清和组织糖皮质激素（皮质醇）的相关并发失衡之间的关系。我们要求考虑将该提案用于R21资金，用于探索性研究生理神经免疫学的应用，以了解结核病感染期间免疫调节疾病病理学的基础。

DESCRIPTION (provided by applicant): The observation of glucocorticoid modulation during tuberculosis infection has been known for many years, however the relationship between glucocorticoid immunomodulation and destructive pathological and granulomatous responses to mycobacterial antigens remains poorly understood. Indeed, relative amounts of both systemic and tissue specific cortisol may be crucial in susceptibility to tuberculosis, and therefore play a defining role in ensuing pathology. C57BL/6 mice demonstrate a rapid decrease in serum cortisol levels during initiation of granulomatous response during acute experimental infection with virulent Mycobacterium tuberculosis. Investigators have actively pursued agents that mimic immunopathology associated with tuberculosis. One such agent; the natural mycobacterial glycolipid trehalose 3,6'dimycolate (TDM) has been researched extensively as a mediator of biological events and granulomatous responses during disease. We have further identified mycobacterial TDM as able to influence systemic serum cortisol levels. This is the first observation of mediation of a systemic glucocorticoid to a mycobacterial glycolipid, and warrants further investigation. Our preliminary findings indicate a need to explore the influence of cortisol on initial events involved in the immunoregulation and immunopathology due to mycobacterial glycolipid TDM. The goal of this application is therefore to examine the relationship between immune- responses induced by mycobacterial glycolipid and associated concurrent imbalances in both serum and tissue glucocorticoids (cortisol) during development of the pulmonary granulomatous response. We request that this proposal be considered for R21 funding directed towards exploratory research into applications of physioneuroimmunology towards understanding the basis of immunoregulated disease pathology during tuberculosis infection.