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Molecular mechanisms of podocyte injury in FSGS

FSGS足细胞损伤的分子机制

基本信息

批准号：
10264943
负责人：
Anna Greka
金额：
$ 41.26万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264943
关键词：
Address Affect Antioxidants Applications Grants BRAF gene Cell Death Cell membrane Cells Cessation of life Chronic Kidney Failure Clinic Coenzyme Q10 Data Development Enzymes Event FDA approved Focal Segmental Glomerulosclerosis Funding Gene Expression Generations Genetic Goals Grant Human In Vitro Injury Insertional Activations Ion Channel Kidney Kidney Diseases Kidney Failure Lead Lipids MAP Kinase Gene Mediating Mitochondria Mitotic Modeling Molecular Mus Mutation Nephrotic Syndrome Pathway interactions Patients Pharmaceutical Preparations Prevalence Proteinuria Publishing Receptor Signaling Receptor, Angiotensin, Type 1 Retinoic Acid Receptor Signal Pathway Signal Transduction Stress Testing Therapeutic Tissues Up-Regulation Work base disease-causing mutation endoplasmic reticulum stress in vivo innovation insight lipid metabolism loss of function metabolomics new therapeutic target novel novel therapeutics podocyte prevent small molecule stressor targeted treatment transcriptomics

项目摘要

SUMMARY Chronic kidney diseases affect more than 700 million people worldwide, and are a frequent cause of kidney failure and death. A key event leading to kidney failure is filter damage, caused by the loss of podocytes. This is a cause of a kidney disease known as Focal segmental Glomerulosclerosis (FSGS). Despite the growing prevalence of kidney diseases, there are currently no FDA approved therapies to prevent the loss of podocytes. The goal of this grant application is to gain a deep understanding of the molecular mechanisms involved in podocyte injury related to the BRAF signaling pathway, so that it may be targeted for therapeutic benefit. We started with a rare genetic kidney disease caused by mutations in an enzyme called PDSS2. Interestingly, we found that the loss of function of this enzyme causes podocytes to die, resulting in FSGS. We subsequently found that a key molecule in preventing podocyte death is BRAF and a small molecule that activates BRAF, called GDC-0879, can protect podocytes from cell death. In fact, GDC-0879 was able to protect podocytes from several injuries including toxic lipids and other stress-causing molecules. Most excitingly, we now have evidence that GDC-0879 protects mice from podocyte injury and the resulting kidney filter damage (called proteinuria). Here, we will explore the precise molecular mechanisms involved in BRAF-related podocyte injury, and the potential for GDC-0879 to become a treatment for FSGS. Successful completion of this work may provide a new, much needed treatment for FSGS and chronic kidney diseases, and one that may be easily brought to the clinic, since GDC-0879 is already an FDA approved drug for other indications.

概括慢性肾脏病影响着全世界 7 亿多人，并且是常见的原因肾衰竭和死亡。导致肾衰竭的一个关键事件是过滤器损坏，这是由足细胞丢失。这是一种称为局灶节段性肾脏疾病的原因肾小球硬化症（FSGS）。尽管肾脏疾病的患病率不断上升，但目前尚无 FDA 批准的疗法来防止足细胞丢失。本次赠款的目标应用是为了深入了解足细胞涉及的分子机制损伤与 BRAF 信号通路相关，因此可以作为治疗益处的目标。我们从一种罕见的遗传性肾病开始，这种疾病是由一种名为 PDSS2 的酶突变引起的。有趣的是，我们发现这种酶功能的丧失会导致足细胞死亡，从而导致在 FSGS 中。我们随后发现防止足细胞死亡的关键分子是 BRAF 和一种激活 BRAF 的小分子，称为 GDC-0879，可以保护足细胞免于细胞死亡。事实上，GDC-0879 能够保护足细胞免受多种损伤，包括有毒脂质和其他引起压力的分子。最令人兴奋的是，我们现在有证据表明 GDC-0879 可以保护小鼠免受足细胞损伤以及由此导致的肾过滤器损伤（称为蛋白尿）。在这里，我们将探讨 BRAF 相关足细胞损伤的精确分子机制，以及 GDC-0879 成为 FSGS 治疗方法的潜力。这项工作的成功完成可能会为 FSGS 和 FSGS 提供急需的新治疗方法。慢性肾脏疾病，并且是一种很容易带到诊所的疾病，因为 GDC-0879 是已获得 FDA 批准用于其他适应症的药物。