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

项目 4：开发中环境 PPARy 激动剂介导的毒性。

• 批准号: 8289723
• 负责人: Jennifer Schlezinger
• 金额: $ 16.03万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8289723
• 关键词: Adipocytes; Affect; Aging; Agonist; Apoptosis; B-Cell Development; B-Lymphocytes; Bone Marrow; Cell Differentiation process; Cell physiology; Cells; Collaborations; Complex Mixtures; Data; Defect; Development; Dose; Environment; Environmental Pollution; Exposure to; Fatty acid glycerol esters; Gene Expression Profile; Goals; Heterodimerization; Homeostasis; Human; Immune; Immune response; Immune system; Impairment; In Vitro; Individual; Instruction; Intervention; Knowledge; Lead; Life; Ligands; Lymphocyte; Lymphopoiesis; Marrow; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Organ; Osteoblasts; Osteogenesis; Osteoporosis; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Physiology; Prevention; RXR; Receptor Activation; Risk Assessment; Role; Signal Transduction; Site; Stromal Cells; System; Technology; Testing; Therapeutic; Toxic effect; Transgenic Model; Visceral; adipocyte differentiation; aging population; base; bone; bone loss; bone quality; immune function; improved; in vivo; lipid biosynthesis; long bone; man; mono-(2-ethylhexyl)phthalate; novel; osteoblast differentiation; osteogenic; pathogen exposure; phthalates; receptor; reproductive; small hairpin RNA; superfund chemical; toxicant

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.

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。