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）处于调控网络的顶端， 控制骨生理学，但目前尚不清楚骨髓中的PPARy激活如何改变骨生理学。 支持终生B细胞发育的微环境。这是一个重要的问题，作为一个日益增长的 许多环境污染物，包括邻苯二甲酸盐和有机鳍等超级基金化学品， 由于它们能够激活PPARy及其异源二聚化配偶体类视色素X 受体（RXR）。我们的长期目标是了解个体和 超级基金化学品的复杂混合物损害了哺乳动物免疫系统的发育， 这需要在不断暴露于病原体的情况下不断发展。我们的目标是 确定PPARy活化在邻苯二甲酸酯和有机Fin-induced骨髓改变中的作用 physiology.我们假设环境中的PPAR/RXR配体通过两种途径抑制B淋巴细胞生成， 通过诱导早期B细胞凋亡和间接改变骨髓中的 这是一种支持淋巴细胞生成的微环境，导致免疫应答的衰老样抑制。我们 我将通过以下三个具体目标来研究这一假设：1）确定PPAR与 和RXR激活以及多能间充质基质细胞分化的功能后果 通过测定邻苯二甲酸酯、有机锡和 污染物混合物，2）确定环境PPAR/RXR激动剂损害的机制 B淋巴细胞生成，通过定义毒物诱导的细胞凋亡机制， 测试污染物改变的骨髓环境支持B细胞发育的能力，和3） 确定体内暴露于环境中的PPAR/RXR激动剂的机制 骨生理学、淋巴细胞生成和免疫反应，通过检查有机锡诱导的骨缺损 完整性、B细胞发育和B细胞功能。将获得关键知识，以改进人的风险 评估和改善预防骨质流失和免疫损害。

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 organofins, are being recognized for their ability to acfivate 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 acfivafion in phthalate- and organofin-induced alteration of bone marrow physiology. We hypothesize that environmental PPAR/RXR ligands suppress B lymphopoiesis by two mechanisms, directly by inducing apoptosis in eariy 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 acfivation 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 mamow 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.