Advances in the pathogenesis of non-thyroidal illness

非甲状腺疾病发病机制的研究进展

• 批准号: 7554657
• 负责人: PATRIZIO CATUREGLI
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554657
• 关键词: Animals; Applications Grants; Bacterial Infections; Bacterial Model; Binding; Biochemical; Bone Marrow; Burn injury; Cell Maturation; Cells; Cirrhosis; Clinical; Cytokine Signaling; Development; Drops; End stage renal failure; Functional disorder; Hematopoietic; Hypothalamic structure; In Vitro; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Investigation; Knockout Mice; Leptin; Link; Lipopolysaccharides; Measures; Mediator of activation protein; Modeling; Mus; Myocardial Infarction; Natural Immunity; Natural Killer Cells; Pathogenesis; Patients; Proteins; Publishing; Receptor Signaling; Reporting; Rodent; Role; Serum; Signal Pathway; Starvation; Stimulus; Syndrome; Testing; Thyroid Gland; Thyroid Hormones; Time; Toll-Like Receptor Pathway; Toll-like receptors; United States National Academy of Sciences; Wild Type Mouse; Work; base; cytokine; human disease; in vivo; leptin receptor; mast cell; novel; pituitary thyroid axis; reconstitution; respiratory distress syndrome; response

DESCRIPTION (provided by applicant): Non-thyroidal illness (NTI) is a syndrome where thyroid hormone levels drop in response to starvation or illnesses such as bacterial infections and myocardial infarction. The pathogenesis of NTI is incompletely understood. NTI can be modeled in animals by injection of lipopolysaccharide, as a mimic of bacterial infection. We have reported that mast cells are critical players in the pathogenesis of NTI, releasing numerous pro-inflammatory mediators in response to activation of the toll-like receptor pathway. LPS failed to induce NTI in mast cell deficient mice. Reconstituting these mice with normal mast cells restored their ability to develop NTI in response to LPS. More recently we found that leptin, in addition to mast cells, is involved in the pathogenesis of bacterial NTI. In fact, LPS failed to induce NTI in leptin knockout mice. We thus postulate in the present application the existence of a novel interaction between leptin and mast cells. Since leptin induces differentiation and activation of hematopoietic cells, and leptin KO mice has dysfunctional natural killer (NK) cells, we hypothesized leptin KO mice has dysfunctional mast cells leading non- response to inflammatory stimuli. We hypothesize the followings. In specific aim 1 we hypothesize that leptin is required for mast cell maturation. We will test the hypothesis by reconstituting leptin knockout mice with mast cells derived from wild type donors. If leptin is truly required for mast cell maturation, then leptin KO mice will acquire normal mast cells from the transfer and should now develop NTI in response to LPS. In specific aim 2 we hypothesize that leptin is required for mast cell activation at the time of NTI induction. To confirm our hypothesis, we will inject LPS plus leptin into leptin KO or mast cell deficient mice. If both are required, NTI will be observed in leptin KO mice injected LPS plus leptin. We, then, assess if mast cells (BMMC) express functional leptin receptor at protein level. If they express leptin receptor, we will assess if leptin receptor on mast cells is required inducing NTI. To assess it, we will generate BMMC from wild type control, leptin KO, and leptin receptor KO, and reconstitute them into mast cell deficient mice. If leptin receptor on mast cells is required, BMMC from leptin receptor KO mice should not restore NTI. In specific aim 3, we will assess whether the NTI mediator released from mast cells are different in the presence or absence of leptin. This grant application provides a fresh look at the pathogenesis of NTI, delineating the influence of leptin and mast cells on thyroid pathophysiology. Project Narrative: Non-thyroidal illness (NTI) is common syndrome observed in numerous human diseases. Its pathogenesis is poorly understood. In this application we propose a new mechanism for NTI based on the interaction between mast cells and leptin.

描述（由申请人提供）：非甲状腺疾病（NTI）是一种因饥饿或细菌感染和心肌梗死等疾病导致甲状腺激素水平下降的综合征。NTI的发病机制尚不完全清楚。NTI可以通过注射脂多糖在动物体内建立模型，作为细菌感染的模拟物。我们已经报道肥大细胞在NTI的发病机制中起关键作用，在toll样受体通路激活的反应中释放大量促炎介质。LPS不能诱导肥大细胞缺陷小鼠的NTI。重建这些小鼠正常肥大细胞恢复他们的能力发展NTI响应LPS。最近，我们发现除了肥大细胞外，瘦素也参与了细菌性NTI的发病机制。事实上，LPS不能在瘦素敲除小鼠中诱导NTI。因此，在目前的应用中，我们假设瘦素和肥大细胞之间存在一种新的相互作用。由于瘦素诱导造血细胞分化和活化，并且瘦素KO小鼠具有功能失调的自然杀伤细胞（NK），我们假设瘦素KO小鼠具有功能失调的肥大细胞，导致对炎症刺激无反应。我们假设如下。在特定目标1中，我们假设瘦素是肥大细胞成熟所必需的。我们将用来自野生型供体的肥大细胞重组瘦素敲除小鼠来验证这一假设。如果瘦素确实是肥大细胞成熟所必需的，那么瘦素KO小鼠将从转移中获得正常肥大细胞，并且现在应该发展成NTI以响应LPS。在特定目标2中，我们假设瘦素是在NTI诱导时肥大细胞激活所必需的。为了证实我们的假设，我们将在瘦素KO或肥大细胞缺陷小鼠中注射LPS加瘦素。如果两者都需要，则在注射脂多糖加瘦素的瘦素KO小鼠中观察到NTI。然后，我们评估肥大细胞（BMMC）是否在蛋白水平上表达功能性瘦素受体。如果它们表达瘦素受体，我们将评估肥大细胞上的瘦素受体是否需要诱导NTI。为了评估它，我们将从野生型对照、瘦素KO和瘦素受体KO中产生BMMC，并将它们重建为肥大细胞缺陷小鼠。如果肥大细胞上的瘦素受体是必需的，来自瘦素受体KO小鼠的BMMC不应该恢复NTI。在具体目标3中，我们将评估在瘦素存在或不存在时肥大细胞释放的NTI介质是否不同。这项拨款申请为NTI的发病机制提供了一个新的视角，描绘了瘦素和肥大细胞对甲状腺病理生理的影响。

项目成果

Application of innate immune molecules for a new class of drugs: infection, inflammation and beyond.

先天免疫分子在新型药物中的应用：感染、炎症等。

• DOI: 10.2174/187153011794982077
• 发表时间: 2011
• 期刊: Endocrine, metabolic & immune disorders drug targets
• 作者: Kimura,HJ;Suzuki,K;Landek-Salgado,MA;Caturegli,P;Jounai,N;Kobiyama,K;Takeshita,F
• 通讯作者: Takeshita,F