Contribution of nonrenal calcitriol production in chronic inflammation

非肾性骨化三醇产生在慢性炎症中的作用

• 批准号: 10296278
• 负责人: Mark B Meyer
• 金额: $ 47.31万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296278
• 关键词: Acute; Animals; Anti-Inflammatory Agents; Arterial Fatty Streak; Atherosclerosis; Biological; Biology; Blood; COVID-19; CYP27B1 gene; Calcitriol; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Complement; Disease; Disease Progression; Dose; Endocrine; Enhancers; Enzymes; Epigenetic Process; Foam Cells; Genes; Genetic; Genomics; Health; High Fat Diet; Hormones; Human; Immune; Immune response; Infiltration; Inflammation; Inflammatory; Interleukin-1 beta; Kidney; Knockout Mice; Knowledge; Lead; Malignant Neoplasms; Metabolic syndrome; Mus; Necrosis; Onset of illness; Outcome; Outcome Study; Patients; Populations at Risk; Prevention; Process; Production; Regulation; Rupture; Senile Plaques; Signal Transduction; Supplementation; Symptoms; TNF gene; Testing; Tissues; Up-Regulation; Vitamin D; Vitamin D supplementation; Vitamin D3 Receptor; base; calcification; clinically relevant; design; dietary; endoplasmic reticulum stress; follow-up; improved; in vivo; insight; macrophage; monocyte; mouse model; nutrition; nutritional supplementation; oxidized lipid; programs; research study; response; skeletal; stem; uptake

Atherosclerosis is a complicated cardiovascular disease that stems from prolonged chronic inflammation. This inflammation causes and is also the result of activated monocyte/macrophage infiltration through arterial walls which eventually leads to a necrotic core plaque that narrows the lumen and may lead to catastrophic rupture and death. Vitamin D is known to invoke an anti-inflammatory program in cultured macrophages by decreasing factors such as IL-1β and TNFα. Vitamin D activation to calcitriol (1,25(OH)2D3), occurs mainly in the kidney by the CYP27B1 enzyme, however, nonrenal target cells (NRTCs), such as the macrophage, express low levels of this enzyme as well, and therefore may produce calcitriol at low levels, locally. This NRTC produced calcitriol is hypothesized to reduce inflammation and positively impact disease progression. Importantly though, these mechanisms remain very poorly understood. In humans, the interpretation of local production of calcitriol has been confounded by the abundant levels of endocrine calcitriol produced by the kidney. We aim to eliminate these confounding issues by defining the production, features, biological impact and anti-disease potential of local activity in the absence of endocrine calcitriol by utilizing a unique mouse model we have created wherein the endocrine production of calcitriol in the kidney and thus blood levels of the endocrine hormone are highly deficient. Our use of this mouse model will enable us to explore key details of the importance of 25(OH)D3 uptake into NRTC tissues, the levels of calcitriol that are produced in these tissues, and the biological impact of this production in genetically modified mice that are sensitive to high fat diet-induced chronic inflammation and atherosclerosis. Based on the unique opportunity to separate the endocrine production of calcitriol from the NRTC, the overall hypothesis for this research study is that production of locally-acting calcitriol through cell-specific Cyp27b1 genomic enhancers can ameliorate the chronic inflammation associated with a high fat diet and atherosclerotic plaque formation. We will test this hypothesis by first establishing core principles of NRTC calcitriol production through AIM 1: exploiting our endocrine-deficient Cyp27b1 pseudo-null mouse model to investigate the impact of both 25(OH)D3 (substrate) status and vitamin D nutritional supplementation on NRTC synthesis of calcitriol and its genetic local impact, AIM 2: defining the NRTC- regulatory module (NRTC-RM) for Cyp27b1 expression that is functionally distinct from that of the kidney endocrine module and determine the mechanisms, epigenetics, and tissue-specific factors involved, and finally AIM 3: examining the nonrenal production of calcitriol and its impact on inflammation and on atherosclerotic plaque formation and calcification in Ldlr-/- mice in the disease state of high fat diet-induced chronic inflammation. This knowledge will provide support for nonrenal calcitriol benefits and will be clinically relevant in the design of human studies aimed at disease onset prevention and/or amelioration of symptoms during cardiovascular disease progression.

动脉粥样硬化是一种复杂的心血管疾病，源于长期的慢性炎症。这种炎症引起并且也是活化的单核细胞/巨噬细胞渗透通过动脉壁的结果，其最终导致使管腔变窄的坏死核心斑块，并且可能导致灾难性破裂和死亡。已知维生素D可通过降低因子（如IL-1β和TNFα）在培养的巨噬细胞中激活抗炎程序。维生素D活化为骨化三醇（1，25（OH）2D 3）主要发生在肾脏中的CYP 27 B1酶，然而，非肾靶细胞（NRTC），如巨噬细胞，也表达低水平的这种酶，因此可能会产生低水平的骨化三醇，局部。这种NRTC产生的骨化三醇被假设为减少炎症并积极影响疾病进展。但重要的是，这些机制仍然知之甚少。在人类中，对局部产生骨化三醇的解释被肾脏产生的大量内分泌骨化三醇所混淆。我们的目标是消除这些混淆的问题，通过定义的生产，功能，生物学影响和抗疾病的潜力，局部活动的情况下，内分泌骨化三醇，通过利用一个独特的小鼠模型，我们已经创建，其中的内分泌生产骨化三醇在肾脏和血液水平的内分泌激素是高度不足的。我们使用这种小鼠模型将使我们能够探索NRTC组织吸收25（OH）D3的重要性、这些组织中产生的钙三醇水平以及这种产生对转基因小鼠的生物学影响的关键细节。对高脂肪饮食诱导的慢性炎症和动脉粥样硬化敏感。基于将骨化三醇的内分泌产生与NRTC分开的独特机会，本研究的总体假设是，通过细胞特异性Cyp 27 b1基因组增强子产生局部作用的骨化三醇可以改善与高脂饮食和动脉粥样硬化斑块形成相关的慢性炎症。我们将通过首先建立通过AIM 1生产NRTC骨化三醇的核心原则来验证这一假设：利用我们的内分泌缺陷型Cyp 27 b1假无效小鼠模型来研究25（OH）D3和CYP 27 b1的影响。（底物）状态和维生素D营养补充对骨化三醇的NRTC合成及其遗传局部影响，AIM 2：定义Cyp 27 b1表达的NRTC-调节模块（NRTC-RM），其在功能上不同于肾内分泌模块，并确定所涉及的机制、表观遗传学和组织特异性因子，最后是AIM 3：在高脂饮食诱导的慢性炎症疾病状态下，检查骨化三醇的非肾产生及其对炎症和对Ldlr-/-小鼠中动脉粥样硬化斑块形成和钙化的影响。这些知识将为骨化三醇的非肾脏获益提供支持，并将在旨在预防疾病发作和/或改善心血管疾病进展期间症状的人体研究设计中具有临床相关性。