Leads and Target Validation for Vascular Calcification in Chronic Kidney Disease

慢性肾病血管钙化的先导物和靶标验证

基本信息

批准号：
7933886
负责人：
JOSE LUIS MILLAN
金额：
$ 47.72万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7933886
关键词：
Address Aging Alkaline Phosphatase Animal Model Aorta Area Arteries Behavior Therapy Biological Availability Cardiovascular system Cessation of life Chemicals Chronic Kidney Failure Clinical Clinical Management Collagen Type I Culture Media Data Diabetes Mellitus Diphosphates Disease Drug Kinetics Effectiveness Event Foundations Hemodialysis Hydrolysis Injection of therapeutic agent Isoenzymes Kidney Failure Laboratories Lead Link Medial Medical Metabolic Bone Diseases Modeling Morbidity - disease rate National Institute of Diabetes and Digestive and Kidney Diseases Obesity Osteogenesis Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Plasma Prevention Property Public Health Rattus Research Role Site Smooth Muscle Solubility Structure-Activity Relationship Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Translating Translational Research Up-Regulation Validation Vascular Smooth Muscle Vascular calcification Viral base calcification drug discovery extracellular high throughput screening improved in vivo infancy inhibitor/antagonist mortality mouse model novel novel strategies overexpression phosphatase inhibitor prevent promoter public health relevance pyrophosphatase scaffold small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): "Translational Science", and specific Challenge Topic, 15-DK-103: "Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies". More specifically, this application proposes to validate a therapeutic target and to improve the bioavailability and pharmacokinetic properties of novel small molecule compounds for the prevention and treatment of calcification of the medial layer of arteries, a common and severe condition in patients with chronic kidney disease (CKD), diabetes, obesity and aging that correlates with cardiovascular events and death. To-date there is no effective medical treatment for medial calcification. Research in our laboratories has demonstrated that vascular calcification is normally inhibited by extracellular pyrophosphate (PPi) produced by vascular smooth muscle. Plasma PPi concentrations are reduced in hemodialysis patients and are inversely correlated with vascular calcification. We have shown that levels of PPi are reduced in uremic vascular smooth muscle and that medial calcification in uremic rats and in mouse models of PPi-deficiency is prevented by injections of PPi. The key regulator of extracellular PPi is the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) that hydrolyzes PPi, thus destroying its ability to suppress calcification. We have also shown that addition of TNAP to culture medium or overexpression of TNAP by viral transduction causes calcification in cultured aortas and transgenic expression of TNAP in tissues expressing type I collagen is sufficient to cause extraosseous calcification. We have also shown that TNAP is pathophysiologically upregulated at sites of medial calcification in uremic aortas and mouse models of idiopathic infantile arterial calcification, suggesting the putative pathophysiological mechanism that links PPi deficiency to medial calcification in patients with CKD. Using high throughput screening, we have identified potent inhibitors of TNAP that completely prevent calcification of aortas in culture. We hypothesize that medial vascular calcification in renal failure results from increased activity of TNAP in the vasculature and that this ectopic calcification can be prevented by inhibitors of TNAP's pyrophosphatase activity. This RC1 proposal focuses sharply on validating TNAP as a therapeutic target and in improving, via Medicinal Chemistry and structure-activity-relationship studies, the bioavailability and pharmacokinetic properties of novel TNAP inhibitors to enable in vivo testing of the effectiveness of this mechanism-based therapeutic strategy in a uremic rat model of CKD. The clinical management of medial calcification has been limited to minimizing the impact of the associated metabolic bone disease to which it is inextricably linked. This indirect approach has not been very effective in CKD and does not address the calcification that occurs in diabetes or with aging. Thus, there is a need for more specific therapies that directly address the pathogenesis of medial calcification. Pharmacological inhibition of TNAP is a novel approach to this problem that directly addresses the upregulation of TNAP in the vasculature and the ensuing PPi deficiency seen in renal failure. Because TNAP controls extracellular PPi levels under normal conditions this therapy is expected to increase local PPi levels in the vasculature thus inhibiting medial calcification. - Relevance to Public Health Medial calcification of the vasculature is of common occurrence in renal failure, diabetes, obesity and aging, where it contributes to morbidity and mortality through compromised arterial function. Currently there are no treatments for this prevalent condition. Our studies will validate a therapeutic target for medial calcification and will optimize new lead chemicals to prevent/treat arterial calcification in established animal models, thus filling this unmet clinical need. PUBLIC HEALTH RELEVANCE: Medial calcification of the vasculature is of common occurrence in renal failure, diabetes, obesity and aging, where it contributes to morbidity and mortality through compromised arterial function. Currently there are no treatments for this prevalent condition. Our studies will validate a therapeutic target for medial calcification and will optimize new lead chemicals to prevent/treat arterial calcification in established animal models, thus filling this unmet clinical need.

描述（由申请人提供）：此申请涉及广泛的挑战领域（15）：“转化科学”和特定的挑战主题，15-DK-103：“在NIDDK疾病的发病机理中转化新分子和途径的发现为潜在的疗法” 。更具体地说，该应用建议验证治疗靶标，并改善新型小分子化合物的生物利用度和药代动力学特性，以预防和治疗动脉内侧动脉内侧的钙化，这是慢性肾脏疾病患者的常见和严重状况（ CKD），与心血管事件和死亡相关的糖尿病，肥胖和衰老。迄今为止，没有有效的内侧钙化治疗方法。在我们的实验室中的研究表明，血管钙化通常受到血管平滑肌产生的细胞外焦磷酸（PPI）的抑制。血液透析患者的血浆PPI浓度降低，并与血管钙化成反比。我们已经表明，PPI的水平在尿毒症血管平滑肌中降低，尿毒症大鼠的内侧钙化和PPI的小鼠模型中的小鼠模型在PPI的注射中预防。细胞外PPI的关键调节剂是脑酶组织非特异性碱性磷酸酶（TNAP），可将PPI水解，从而破坏其抑制钙化的能力。我们还表明，通过病毒转导将TNAP添加到TNAP中的培养基或过表达TNAP会导致培养的主动脉中钙化和表达I型胶原蛋白的组织中TNAP的转基因表达，足以引起胸膜外钙化。我们还表明，TNAP在尿毒症主动脉中内侧钙化部位和特发性婴儿动脉钙化的小鼠模型的病理生理上上调，这表明CKD患者的PPI缺乏症与内侧钙化联系起来的假定病理生理机制。使用高吞吐量筛选，我们已经确定了TNAP的有效抑制剂，该抑制剂完全阻止了培养物中主动脉的钙化。我们假设肾衰竭中的内侧血管钙化是由于TNAP的焦磷酸酶活性的抑制剂可以预防TNAP活性的增加，并且该异位钙化可以预防。该RC1提案非常着重于验证TNAP作为一种治疗靶点，并通过药物化学和结构激活关系研究改善了新型TNAP抑制剂的生物可用性和药代动力学特性，以启用这种机制治疗性治疗的有效性CKD的尿毒症大鼠模型中的策略。内侧钙化的临床管理仅限于最大程度地减少与之相关的代谢骨疾病的影响。这种间接方法在CKD中不是很有效，也不能解决糖尿病或衰老中发生的钙化。因此，需要更具体的疗法直接解决内侧钙化的发病机理。 TNAP的药理学抑制是解决此问题的一种新方法，它直接解决了脉管系统中TNAP的上调以及肾衰竭中随之而来的PPI缺乏。由于TNAP在正常条件下控制细胞外PPI水平，因此该疗法预计会增加脉管系统中的局部PPI水平，从而抑制内侧钙化。 - 与公共卫生的脉管系统内侧钙化相关，在肾衰竭，糖尿病，肥胖和衰老中很常见，在这种情况下，它通过受损的动脉功能促进了发病率和死亡率。目前，没有针对这种普遍状况的治疗方法。我们的研究将验证中间钙化的治疗靶标，并将优化新的铅化学物质，以预防/治疗既定动物模型中的动脉钙化，从而满足这种未满足的临床需求。公共卫生相关性：脉管系统的内侧钙化在肾功能衰竭，糖尿病，肥胖和衰老中很常见，在这种情况下，它通过受损的动脉功能促进了发病率和死亡率。目前，没有针对这种普遍状况的治疗方法。我们的研究将验证中间钙化的治疗靶标，并将优化新的铅化学物质，以预防/治疗既定动物模型中的动脉钙化，从而满足这种未满足的临床需求。