Innovative Approaches to Treating Alport Syndrome

治疗阿尔波特综合征的创新方法

• 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
• 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

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.

项目摘要 肾脏疾病是全球健康问题，越来越普遍。一级肾小球 遗传和获得的疾病代表了很大一部分病例。我们对 了解肾小球滤过屏障的构成及其如何损坏，漏水到 血浆蛋白，有时是非功能性的。我们的重点是调查组成和 肾小球基底膜（GBM）的功能，这是一种专门的细胞外基质 肾脏过滤屏障的组成部分。 GBM包含胶原蛋白IV，层粘连蛋白，Nidogen和 硫酸乙酰肝素蛋白聚糖蛋白，可能数十个其他不太丰富的基质蛋白。虽然 GBM是由足细胞和肾小球内皮细胞合成的，它仅是足细胞 这使主要的胶原蛋白IV同工型由3，4和5链组成的链组成 形成一个分泌的异三聚体。影响GBM的胶原蛋白IV成分的突变会导致Alport 综合征，导致末期肾脏疾病（ESKD）以及听力和眼睛缺陷。这 据估计，Alport综合征的患病率是5,000至10,000名新生儿中的1个，因此有 全球成千上万的患者。结构性GBM异常是继发的 胶原蛋白IV缺陷导致GBM的增厚和分裂，最终导致Podocyte脚步过程 递增，肾小球硬化和细胞隆的纤维化。直到最近还没有治疗 用于Alport综合征。但是，对小鼠和狗的研究表明，ACE抑制作用会减慢肾脏 疾病发展到ESKD。这些动物研究已在人类Alport综合征中得到验证 ACE抑制剂或血管紧张素II受体阻滞剂的患者被认为是 关心。尽管这种治疗突破延迟了ESKD，但这并不能治愈。仍然需要新的 靶向疗法。该提案的目的是使用涉及的创新，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 一定要通过去除致病成分来改变其正常组成或改变其组成。 无论哪种情况，人们的期望是改善GBM组成至少将部分正常化GBM 结构和功能。与肾素 - 血管紧张素系统封锁一起作为护理标准，这些 治疗应大大推迟ESKD的时间，并对患者有益。