Innovative Approaches to Treating Alport Syndrome

治疗阿尔波特综合征的创新方法

基本信息

批准号：
10375906
负责人：
JEFFREY H MINER
金额：
$ 45.37万
依托单位：
WASHINGTON UNIVERSITY
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：
2021-09-22 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375906
关键词：
Affect Agrin Aminoglycosides Angiotensin II Receptor Angiotensin-Converting Enzyme Inhibitors Animals Attenuated Basement membrane Biomedical Research COL4A3 gene CRISPR/Cas technology Canis familiaris Cells Childhood Clinical Clinical Trials Cochlea Collagen Collagen Type IV Cultured Cells Data Defect Dialysis procedure Disease Disease Progression Drug Combinations Ear End stage renal failure Endothelial Cells Engineering Excision Exposure to Extracellular Matrix Eye Failure Fibrosis Filtration Foot Process Gene Mutation Genes Genetic Genetic Diseases Genetic Translation Goals Health Hearing Hearing problem Heparan Sulfate Proteoglycan Hereditary Disease Hereditary nephritis Human Inherited Injury Intravenous Investigation Kidney Kidney Diseases Kidney Failure Laminin Lead Link Liver Mediating Membrane Structure and Function Mus Mutant Strains Mice Mutation Mutation Analysis Newborn Infant Nidogen Nonsense Codon Nonsense Mutation Organism Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Plasma Proteins Predisposition Prevalence Process Protein Biochemistry Protein Isoforms Proteins Publishing Quality of life Recombinants Renal glomerular disease Renin-Angiotensin System Reporting Research Retina Ribosomes Secondary to Structure Syndrome System Technology Terminator Codon Testing Time Transplantation Tubular formation design expectation experimental study gene repair genome editing glomerular basement membrane glomerular endothelium glomerular filtration glomerular function glomerulosclerosis homologous recombination improved in vivo innovation interest lens mouse model mutant new technology new therapeutic target novel strategies novel therapeutic intervention novel therapeutics nuclease personalized medicine podocyte postnatal period premature repaired side effect small molecule standard of care stem cells success therapeutic evaluation

项目摘要

Project Summary Kidney disease is worldwide health problem that is becoming increasingly common. Primary glomerular disease, both genetic and acquired, represents a significant proportion of cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged, leaky to plasma proteins, and eventually non-functional. Our focus has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the kidney’s filtration barrier. The GBM contains collagen IV, laminin, nidogen, and the heparan sulfate proteoglycan agrin, and likely dozens of other less abundant matrix proteins. Although the GBM is synthesized by both podocytes and glomerular endothelial cells, it is exclusively podocytes that make the major collagen IV isoform, which consists of the 3, 4, and 5 chains that assemble to form a secreted heterotrimer. Mutations that affect this collagen IV component of the GBM cause Alport syndrome, which leads to end-stage kidney disease (ESKD) as well as hearing and eye defects. The prevalence of Alport syndrome has been estimated to be 1 in 5,000 to 10,000 newborns, so there are hundreds of thousands of affected patients around the world. Structural GBM abnormalities secondary to the collagen IV defect lead to thickening and splitting of the GBM and eventually podocyte foot process effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Until recently there has been no treatment for Alport syndrome. However, studies in mice and dogs had shown that ACE inhibition slows kidney disease progression to ESKD. These animal studies have been validated in human Alport syndrome patients, for whom ACE inhibitors or angiotensin II receptor blockers are now considered the standard of care. Despite this treatment breakthrough that delays ESKD, it is not a cure; there is still a need for new targeted therapies. The goal of this proposal is to use innovative, state of the art technologies that involve small molecule, genetic, and protein biochemistry approaches to attempt to either restore the Alport GBM to a somewhat normal composition or to alter its composition through removal of pathogenic components. In either case, the expectation is that improving GBM composition will at least partially normalize GBM structure and function. Together with renin-angiotensin system blockade as a standard of care, these treatments should greatly delay the time to ESKD and be beneficial for patients.

项目概要肾脏疾病是越来越常见的世界性健康问题。遗传性和获得性疾病占我们感兴趣的病例的很大一部分。了解肾小球滤过屏障的构成及其如何受损、渗漏血浆蛋白，并最终失去功能，我们的重点是研究其组成和功能。肾小球基底膜 (GBM) 的功能，是一种特殊的细胞外基质 GBM 是肾脏过滤屏障的组成部分，含有 IV 型胶原蛋白、层粘连蛋白、巢蛋白和巢蛋白。硫酸乙酰肝素蛋白聚糖集聚蛋白，可能还有数十种其他含量较低的基质蛋白。 GBM由足细胞和肾小球内皮细胞共同合成，仅由足细胞合成形成主要的 IV 型胶原同工型，由 α3、α4 和 α5 链组成，这些链组装成形成影响 GBM 胶原蛋白 IV 成分的分泌型异源三聚体，导致 Alport。综合征，导致终末期肾病 (ESKD) 以及听力和眼部缺陷。据估计，奥尔波特综合征的患病率为每 5,000 至 10,000 名新生儿中就有 1 人患有阿尔波特综合征，因此全世界有数十万继发于 GBM 结构异常的患者。 IV 型胶原蛋白缺陷导致 GBM 增厚和分裂，最终导致足细胞足突直到最近还没有治疗方法。然而，针对小鼠和狗的研究表明，ACE 抑制会减缓肾功能。这些动物研究已在人类奥尔波特综合征中得到验证。对于这些患者，ACE 抑制剂或血管紧张素 II 受体阻滞剂现在被视为标准治疗尽管这一治疗突破延迟了 ESKD，但仍然需要新的治疗方法。该提案的目标是使用涉及的创新、最先进的技术。小分子、遗传和蛋白质生物化学方法试图恢复 Alport GBM 到某种程度正常的成分或通过去除致病成分来改变其成分。无论哪种情况，预期改善 GBM 成分将至少部分使 GBM 正常化结构和功能。与肾素-血管紧张素系统阻断一起作为护理标准，这些治疗应大大延迟 ESKD 的时间并对患者有益。