Project 4: Environmental PPARy Agonist-Mediated Toxicity in the Dev. Immune Syst

过氧化物酶体增殖物激活受体γ（PPARy）处于控制骨生理学的调节网络的顶点，但仍不清楚骨髓中PPARy的激活如何改变支持终身B细胞发育的微环境。这是一个重要的问题，因为越来越多的环境污染物，包括超级基金化学品，如邻苯二甲酸酯和有机锡，被认为具有激活PPARy及其异源二聚化伴侣类维生素A X受体（RXR）的能力。我们的长期目标是了解超级基金化学品的单个和复杂混合物损害哺乳动物免疫系统发育的分子机制，该系统需要在持续的病原体暴露面前持续发展。目的是确定PPARy活化在邻苯二甲酸酯和有机锡诱导的骨髓生理学改变中的作用。我们假设环境中的PPAR/RXR配体通过两种机制抑制B淋巴细胞生成，直接通过诱导早期B细胞凋亡，间接通过改变支持淋巴细胞生成的骨髓微环境，导致免疫应答的衰老样抑制。我们将通过追求三个具体目标来研究这一假设：1）通过测定邻苯二甲酸酯、有机锡和污染物混合物诱导的成骨转录组的变化，确定PPAR和RXR活化与多能间充质基质细胞分化的功能后果之间的关系，2）确定环境PPAR/RXR激动剂损害B淋巴细胞生成的机制，通过定义毒物诱导的细胞凋亡的机制和通过测试污染物改变的骨髓环境支持B细胞发育的能力来直接和间接地进行，和3）确定体内暴露于环境PPAR/RXR激动剂负面影响骨生理学的机制，通过检查有机锡诱导的骨完整性、B细胞发育和B细胞功能缺陷，评估淋巴细胞生成和免疫应答。将获得关键知识，以完善人类风险评估，并改善对骨质流失和免疫损害的预防。

Peroxisome proliferator activated receptor y (PPARy) is poised at the apex of a regulatory network that controls bone physiology, yet it remains unclear how activation of PPARy in the bone marrow may alter the microenvironment that supports life-long B cell development. This is an important problem, as a growing number of environmental contaminants, including Superfund chemicals such as phthalates and organotins, are being recognized for their ability to activate PPARy and its heterodimerization partners the retinoid X receptors (RXR). Our long-term goal is to understand the molecular mechanisms by which individual and complex mixtures of Superfund chemicals impair development in the mammalian immune system, a system that requires ongoing development in the face of continuing pathogen exposures. The objective here is to determine the role of PPARy activation in phthalate- and organotin-induced alteration of bone marrow physiology. We hypothesize that environmental PPAR/RXR ligands suppress B lymphopoiesis by two mechanisms, directly by inducing apoptosis in early B cells and indirectly by altering the bone marrow microenvironment that supports lymphopoiesis, resulting in aging-like suppression of immune responses. We will investigate this hypothesis by pursuing three Specific Aims: 1) Determine the relationship between PPAR and RXR activation and the functional consequences for multipotent mesenchymal stromal cell differentiation by determining changes in the osteogenic transcriptome induced by a phthalate, an organotin, and contaminant mixtures, 2) Determine the mechanisms by which environmental PPAR/RXR agonists damage B lymphopoiesis, both directly and indirectly by defining mechanisms of toxicant-induced apoptosis and by testing contaminant-altered bone marrow environments for the ability to support B cell development, and 3) Determine mechanisms by which in vivo exposure to environmental PPAR/RXR agonists negatively affects bone physiology, lymphopoiesis and immune responses by examining organotin-induced defects in bone integrity, B cell development and B cell function. Critical knowledge will be gained to refine human risk assessment and to improve prevention of both bone loss and immune compromise.