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y(PPARy)处于控制骨生理的调控网络的顶端，但目前尚不清楚PPARy在骨髓中的激活如何改变支持终生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，正被认为具有激活PPARy及其异二聚化伙伴维甲酸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，面对持续的病原体暴露，该系统需要持续发展。本研究的目的是确定PPARy激活在邻苯二甲酸盐和有机锡诱导的骨髓生理改变中的作用。我们假设，环境中的PPAR/RXR配体通过两种机制抑制B淋巴细胞的生成，直接通过诱导早期B细胞的凋亡，间接通过改变支持淋巴细胞生成的骨髓微环境，导致免疫反应的老化抑制。我们将通过追求三个特定的目标来研究这一假说：1)通过确定邻苯二甲酸盐、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激活之间的关系以及对多能间充质基质细胞分化的功能后果；2)通过定义毒物诱导的细胞凋亡的机制和通过测试污染改变的骨髓环境支持B细胞发育的能力，确定环境中的PPAR/RXR激动剂直接或间接损害B淋巴细胞生成的机制；以及3)通过检查有机锡诱导的骨完整性缺陷，确定在体内暴露于环境PPAR/RXR激动剂对骨生理、淋巴生成和免疫反应产生负面影响的机制。B细胞发育和B细胞功能。将获得关键知识，以完善人类风险评估，并改善对骨丢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.