Advances in the pathogenesis of non-thyroidal illness

描述（由申请人提供）：非甲状腺疾病（NTI）是一种甲状腺激素水平因饥饿或细菌感染和心肌梗死等疾病而下降的综合征。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物。我们已经报道了肥大细胞在NTI的发病机制中是关键的参与者，其响应于Toll样受体途径的激活而释放许多促炎介质。LPS不能诱导肥大细胞缺陷小鼠的NTI。用正常肥大细胞重建这些小鼠恢复了它们响应LPS而产生NTI的能力。最近，我们发现，瘦素，除了肥大细胞，是参与细菌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，我们假设瘦素KO小鼠具有功能失调的肥大细胞，导致对炎症刺激无应答。我们假设如下。在具体目标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供体的肥大细胞重建瘦素基因敲除小鼠来检验这一假设。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，并且现在应该响应于LPS而发展NTI。在具体目标2中，我们假设瘦素是NTI诱导时肥大细胞活化所需的。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，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。为了评估它，我们将从野生型对照、瘦素KO和瘦素受体KO产生BMMC，并将它们重建成肥大细胞缺陷型小鼠。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。在具体的目标3中，我们将评估从肥大细胞释放的NTI介体在存在或不存在瘦素的情况下是否不同。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。其发病机制知之甚少。在这个应用中，我们提出了一个新的机制，NTI的基础上肥大细胞和瘦素之间的相互作用。

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.