DIETARY ZINC-ITS EFFECTS ON THE IMMUNE RESPONSE

膳食锌对免疫反应的影响

• 批准号: 7087052
• 负责人: PAMELA Jean FRAKER
• 金额: $ 33.9万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087052
• 关键词: B lymphocyte; BCL2 gene /protein; apoptosis; cell differentiation; cell proliferation; clinical research; corticosteroid receptors; dietary mineral; flow cytometry; gene expression; genetically modified animals; glucocorticoids; granulocyte; hematopoiesis; human subject; immunity; intracellular transport; laboratory mouse; lymphopoiesis; malnutrition; microarray technology; monocyte; nutrition related tag; phagocytosis; transcription factor; zinc

DESCRIPTION (provided by applicant): The zinc deficient mouse (ZD) is a valuable model for elucidating the molecular and biochemical changes made by the immune system to provide a core of host defense in the face of suboptimal nutriture. Accelerated apoptosis disrupts lymphopoiesis creating lymphopenia, but splenic lymphocytes of the ZD mouse have greater potency. Conversely, myelopoietic cells that provide innate immunity remain intact maintaining zinc homeostasis. The studies below represent the first experiments to explore in depth the effect of suboptimal nutriture on hematopoietic processes. 1. Lymphopoiesis: The role of apoptosis in disrupting lymphopoiesis will be further defined in vivo using a transgenic mouse over-expressing the anti-apoptotic protein Bcl-2 in cells of the B-lineage allowing us to compare the survival of protected pre B cells versus unprotected pre T cells during ZD. Pro B cells which accumulated in ZD mice will be examined for expression of Pax 5, a transcription factor key to B cell development. We suspect it is low in pro B cells from ZD mice allowing them to engage in lineage reversal joining the ever increasing pool of myeloid cells. We also suspect phenotypic analysis of progenitor cells in ZD mice will show they are also skewed towards myelopoiesis. 2. Myelopoiesis: The rate of production of monocytic and granulocytic cells in ZD mouse will be ascertained to see if the rates are actually accelerated as data suggests. Experiments are proposed to determine the intrinsic zinc content of these cells and the role of zinc transporters in enabling them to differentiate and proliferate in a zinc depleted environment. Changes in gene expression especially the glucocorticoid receptor (GcR) will be evaluated to better understand how these cells survive in a low zinc environment that includes elevated glucocorticoids (Gc). Objective 3. Evaluate the Impact of Low Zinc (LZ) versus Gc on Myelopoiesis. One cannot decipher the impact of LZ versus accompanying Gc on cells in vivo. Therefore, a LZ culture has been developed to which Gc can be added to decipher the effects of each alone and in combination on these aspects of myelopoiesis (a) effects on maturation - proliferation, (b) effects on function to include the oxygen burst and phagocytosis, (c) effects on expression of GcR (data indicate myeloid cells survive Gc-induced apoptosis by down regulating GcR), (d) cDNA microarray analysis of changes in expression of 200 genes involved in cell survival and apoptosis. Objective 4. Adaptation Strateqies of Splenic Lymphocytes. Naive T and B cells from ZD mice will be examined for enhanced expression of la, IgM, BCR, TCR, CD3, IL-2R, CD40 and CD40L, etc., which could account for their heightened responses. The basal rate of apoptosis, ability to withstand an active apoptotic challenge, potency of response to antigenic challenges will be evaluated to see if splenic T and B cells of the ZD mouse have developed adaptations to their harsh environment.

描述（由申请人提供）：锌不足小鼠（ZD）是一个有价值的模型，用于阐明免疫系统的分子和生化变化，以在面对次优营养的情况下提供宿主防御的核心。加速的凋亡会破坏产生淋巴细胞减少症的淋巴细胞，但ZD小鼠的脾淋巴细胞具有更大的效力。相反，提供先天免疫力的脊髓细胞保持锌稳态保持完整。下面的研究代表了最深入探索次级营养对造血过程的作用的第一个实验。 1。淋巴管：使用过表达抗凋亡蛋白Bcl-2在B-lineage细胞中，将在体内进一步定义凋亡在破坏淋巴细胞中的作用，从而使我们可以比较受保护的Prebotus prebotus preptus preptus preptic prepted prected prepted prepted prepted prepted prepted prected prected prected prected prected prected prected prected te。将检查积累在ZD小鼠中的Pro B细胞，以表达PAX 5，这是B细胞发育的转录因子键。我们怀疑它在ZD小鼠的Pro B细胞中含量很低，使它们可以参与谱系逆转，以加入不断增加的髓样细胞。我们还怀疑ZD小鼠中祖细胞的表型分析将表明它们也偏向骨髓。 2。脊髓脉：将确定ZD小鼠中单核细胞和粒细胞细胞的生产速率，以查看该速率是否如数据所示，是否实际上加速了速率。提出了实验来确定这些细胞的固有锌含量，以及锌转运蛋白在使其在锌耗尽环境中分化和增殖中的作用。将评估基因表达的变化，尤其是糖皮质激素受体（GCR），以更好地了解这些细胞如何在包括升高的糖皮质激素（GC）的低锌环境中存活。目标3。评估低锌（LZ）与GC对骨髓卵的影响。一个人不能破译LZ与伴随GC对体内细胞的影响。 Therefore, a LZ culture has been developed to which Gc can be added to decipher the effects of each alone and in combination on these aspects of myelopoiesis (a) effects on maturation - proliferation, (b) effects on function to include the oxygen burst and phagocytosis, (c) effects on expression of GcR (data indicate myeloid cells survive Gc-induced apoptosis by down regulating GcR), (d) cDNA微阵列分析了参与细胞存活和凋亡的200个基因表达的变化。目标4。脾淋巴细胞的适应策略。将检查来自ZD小鼠的幼稚T和B细胞，以增强LA，IgM，BCR，TCR，CD3，IL-2R，CD40和CD40L等的表达，这可以解释其响应的增强。将评估凋亡的基础速率，承受主动凋亡挑战的能力，对抗原挑战的反应效力，以查看ZD小鼠的脾脏T和B细胞是否已经适应了其恶劣环境。