Advances in the pathogenesis of non-thyroidal illness

非甲状腺疾病发病机制的研究进展

基本信息

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
项目类别：
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

项目摘要

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塞等疾病而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中建模，作为细菌感染的模拟。我们已经报道，肥大细胞在 NTI 发病机制中发挥着关键作用，响应 Toll 样受体途径的激活而释放大量促炎介质。 LPS 未能在肥大细胞缺陷小鼠中诱导 NTI。用正常肥大细胞重建这些小鼠，恢复了它们响应 LPS 产生 NTI 的能力。最近我们发现，除了肥大细胞之外，瘦素也参与细菌 NTI 的发病机制。事实上，LPS 未能在瘦素敲除小鼠中诱导 NTI。因此，我们在本申请中假设瘦素和肥大细胞之间存在新的相互作用。由于瘦素诱导造血细胞的分化和活化，并且瘦素 KO 小鼠具有功能失调的自然杀伤 (NK) 细胞，因此我们假设瘦素 KO 小鼠具有功能失调的肥大细胞，导致对炎症刺激无反应。我们做出以下假设。在具体目标 1 中，我们假设肥大细胞成熟需要瘦素。我们将通过用来自野生型供体的肥大细胞重建瘦素敲除小鼠来检验这一假设。如果肥大细胞成熟确实需要瘦素，那么瘦素 KO 小鼠将从移植中获得正常的肥大细胞，并且现在应该响应 LPS 产生 NTI。在具体目标 2 中，我们假设 NTI 诱导时肥大细胞激活需要瘦素。为了证实我们的假设，我们将 LPS 加瘦素注射到瘦素 KO 或肥大细胞缺陷小鼠中。如果两者都需要，则将在注射 LPS 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) 是否在蛋白质水平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。为了对其进行评估，我们将从野生型对照、瘦素 KO 和瘦素受体 KO 中生成 BMMC，并将它们重建为肥大细胞缺陷小鼠。如果需要肥大细胞上的瘦素受体，来自瘦素受体 KO 小鼠的 BMMC 不应恢复 NTI。在具体目标 3 中，我们将评估肥大细胞释放的 NTI 介质在瘦素存在或不存在的情况下是否不同。该拨款申请为 NTI 的发病机制提供了新的视角，描述了瘦素和肥大细胞对甲状腺病理生理学的影响。项目叙述：非甲状腺疾病（NTI）是在许多人类疾病中观察到的常见综合征。其发病机制尚不清楚。在本申请中，我们提出了一种基于肥大细胞和瘦素之间相互作用的 NTI 新机制。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Kimura,HJ;Suzuki,K;Landek-Salgado,MA;Caturegli,P;Jounai,N;Kobiyama,K;Takeshita,F
通讯作者：
Takeshita,F