Kidney PCSK9 in nephrotic syndrome

肾病综合征中的肾脏 PCSK9

基本信息

批准号：
10542792
负责人：
Lionel Claudius Clement
金额：
$ 34.54万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542792
关键词：
Affinity Amiloride Animal Model Antibodies Archives Biopsy Blood Circulation Breeding Cell Line Cell surface Cells Cholesterol Confocal Microscopy Detection Development Diabetic Nephropathy Diagnosis Disease Duct (organ) structure Family Focal and Segmental Glomerulosclerosis Gel Glomerulonephritis Hepatic Human Intestines Kidney Kidney Diseases Link Liver Longitudinal Studies Low Density Lipoprotein Receptor Mass Spectrum Analysis Membranous Glomerulonephritis Modeling Molecular Molecular Chaperones Mus Nephrosis Nephrotic Syndrome Patient Care Patient Selection Patients Pattern Pharmaceutical Preparations Phase Phosphorylation Plasma Play Post-Translational Protein Processing Proprotein Convertases Protein Secretion Proteins Proteinuria Puromycin Aminonucleoside Rattus Recombinants Renal glomerular disease Rodent Rodent Model Role Sampling Serine Protease Serum Sodium Subtilisins Sulfate Testing Therapeutic Tissues Urine cell cortex comparison control db/db mouse epithelial Na+ channel gain of function mutation heart disease risk hypercholesterolemia hypocholesterolemia improved kidney biopsy kidney cortex member migration nephrotoxicity prevent protein expression sialylation standard care two-dimensional

项目摘要

Summary / Abstract (max 30 lines): Nephrotic syndrome is a major manifestation of human glomerular disease, and patients with this condition develop large amounts of protein in the urine (proteinuria) and elevated levels of plasma cholesterol (hypercholesterolemia). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is well studied in the liver where it is implicated in the development of hypercholesterolemia but little is known about the link between kidney PCSK9 and hypercholesterolemia. Statins and/or PCSK9 antibodies are now considered the standard care for patients with hypercholesterolemia but this therapeutic approach only treats hypercholesterolemia once it is established and does not prevent the development of hypercholesterolemia. Recent studies from the applicant’s lab suggest that PCSK9 is expressed in the kidney, mainly in the cortical collecting duct (CCD) and that PCSK9 secreted from the CCD initiates hypercholesterolemia in nephrotic syndrome. In fact, PCSK9 expression is increased in the CCD in human focal and segmental glomerulosclerosis (FSGS) kidney biopsies compared to controls. This phenomenon was also noted in two animal models of FSGS. In this proposal, the PI will study molecular mechanisms of the origin of hypercholesterolemia of nephrotic syndrome and will identify the specific glycomic profile of CCD-secreted PCSK9. It will allow its detection and depletion during the early phase of hypercholesterolemia to prevent or reduce progression to the established phase. In Specific Aim 1, the applicant will study by confocal microscopy, the expression of CCD-PCSK9 in biopsies from nephrotic patients with other kidney diseases and corresponding animal models. In Specific Aim 2, the applicant will use mass spectrometry to identify the specific post-translational modification profile of PCSK9 secreted from the kidney CCD. The affinity of LDL receptor for different forms of recombinant PCSK9, that mimic liver or kidney secreted proteins, will also be assed. In Specific Aim 3, the applicant will study the effect of modulating CCD-PCSK9 expression and its depletion from plasma on sustained hypercholesterolemia in nephrotic syndrome.

摘要 /摘要（最大30行）：肾病综合征是人肾小球疾病的主要表现，患有这种情况的患者在尿液（蛋白尿）和血浆胆固醇水平升高中形成大量蛋白质（高胆固醇血症）。普罗蛋白转化酶枯草蛋白/KEXIN 9型（PCSK9）在肝脏中很好地研究了它暗示在高胆固醇血症的发展中，但对肾脏之间的联系知之甚少 PCSK9和高胆固醇血症。他汀类药物和/或PCSK9抗体现在被认为是标准护理高胆固醇血症的患者，但这种治疗方法仅治疗高胆固醇血症建立并且不能阻止高胆固醇血症的发展。申请人实验室的最新研究表明，PCSK9在肾脏中表达，主要是在皮质中收集管道（CCD）和从CCD分泌的PCSK9在肾病中启动高胆固醇血症综合征。实际上，在人类局灶性和节段性肾小球硬化中，CCD中PCSK9的表达增加（FSG）肾脏活检与对照组相比。在两个FSG的动物模型中也注意到了这种现象。在此提案中，PI将研究肾病高胆固醇血症起源的分子机制综合征，并将确定CCD分泌PCSK9的特定糖菌谱。它将允许其检测和高胆固醇血症早期的耗竭，以防止或减少发展为已建立的阶段。在特定目标1中，申请人将通过共聚焦显微镜研究，CCD-PCSK9在活检中的表达来自患有其他肾脏疾病和相应动物模型的肾病患者。在特定目标2中，申请人将使用质谱法来识别特定的翻译后修改肾脏CCD分泌的PCSK9的轮廓。 LDL受体对不同形式的重组的亲和力 PCSK9（模仿肝脏或肾脏分泌的蛋白质）也将被屁股。在特定的目标3中，申请人将研究调节CCD-PCSK9表达及其耗尽的影响肾病综合征持续性高胆固醇血症的血浆。