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）是一种综合征，甲状腺激素水平响应于饥饿或细菌感染和心肌梗塞等疾病。 NTI的发病机理尚不完全理解。可以通过注射脂多糖作为细菌感染的模仿来对NTI进行建模。我们报告说，肥大细胞是NTI发病机理的关键参与者，释放了许多促炎性介质，以响应Toll样受体途径的激活。 LP无法诱导肥大细胞缺乏小鼠的NTI。用正常肥大细胞重新建立了这些小鼠，恢复了其响应LP的NTI的能力。最近，我们发现，除肥大细胞外，瘦素还参与细菌NTI的发病机理。实际上，LPS未能诱导瘦素基因敲除小鼠的NTI。因此，我们在本应用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激活，而瘦素KO小鼠具有功能障碍的天然杀伤（NK）细胞，因此我们假设瘦素KO小鼠的乳脂细胞具有功能障碍的肥大细胞，导致对炎性刺激的反应。我们假设以下内容。在特定的目标1中，我们假设肥大细胞成熟需要瘦素。我们将通过与野生型供体衍生的肥大细胞重建瘦素基因敲除小鼠来检验假设。如果肥大细胞成熟真正需要瘦素，则瘦素KO小鼠将从转移中获取正常的肥大细胞，现在应响应LPS发展NTI。在特定的目标2中，我们假设在NTI诱导时肥大细胞激活需要瘦素。为了确认我们的假设，我们将将LPS加上瘦素注入瘦素KO或肥大细胞缺乏小鼠。如果两者都需要两者，将在注射的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，我们将从野生型控制，瘦素KO和瘦素受体KO中产生BMMC，并将其重构为缺乏肥大细胞缺乏小鼠。如果需要肥大细胞上的瘦素受体，则瘦素受体KO小鼠的BMMC不应恢复NTI。在特定目标3中，我们将评估在存在或不存在瘦素的情况下，从肥大细胞释放的NTI介质是否有所不同。该赠款的应用提供了对NTI的发病机理的全面研究，描述了瘦素和肥大细胞对甲状腺病理生理学的影响。项目叙事：非甲状腺疾病（NTI）是许多人类疾病中观察到的常见综合征。它的发病机理知之甚少。在此应用中，我们根据肥大细胞与瘦素之间的相互作用提出了一种新的NTI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