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: 7360814
• 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/7360814
• 关键词: Animals; Applications Grants; Bacterial Infections; Bacterial Model; Binding; Biochemical; Bone Marrow; Burn injury; Cell Maturation; Cells; Cirrhosis; Clinical; Condition; Cytokine Signaling; Development; Drops; End stage renal failure; Functional disorder; Hematopoietic; Hypothalamic structure; In Vitro; 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; Newborn Respiratory Distress Syndrome; 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; 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(申请人提供)：非甲状腺疾病(NTI)是一种综合征，甲状腺激素水平下降，以应对饥饿或疾病，如细菌感染和心肌梗死。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身上模拟，作为细菌感染的模仿物。我们已经报道，肥大细胞在NTI的发病机制中起关键作用，它在Toll样受体通路激活后释放大量的促炎介质。脂多糖不能诱导肥大细胞缺陷小鼠NTI。用正常的肥大细胞重组这些小鼠，恢复了它们对脂多糖的反应而发生NTI的能力。最近我们发现，除了肥大细胞外，瘦素还参与了细菌性NTI的发病机制。事实上，脂多糖未能在瘦素基因敲除小鼠中诱导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Leptin可诱导造血细胞分化和激活，而Leptin KO小鼠具有功能异常的自然杀伤(NK)细胞，我们推测Leptin KO小鼠存在功能异常的肥大细胞，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。我们将通过用来自野生型捐赠者的肥大细胞重组瘦素基因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的肥大细胞，现在应该会出现NTI以应对内毒素。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。为了证实我们的假设，我们将向瘦素KO或肥大细胞缺陷小鼠注射脂多糖加瘦素。如果两者都需要，将在注射脂多糖和瘦素的瘦素KO小鼠中观察到NTI。然后，我们在蛋白质水平上评估肥大细胞(BMMC)是否表达功能性瘦素受体。如果他们表达瘦素受体，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。如果肥大细胞上需要瘦素受体，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介体在有无瘦素的情况下是否有所不同。这项拨款申请为NTI的发病机制提供了一个全新的视角，描绘了瘦素和肥大细胞对甲状腺病理生理学的影响。 项目简介：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。在这一应用中，我们提出了一种基于肥大细胞和瘦素相互作用的NTI新机制。