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.

概括慢性肾脏疾病在全球范围内影响超过7亿人，这是一个经常的原因肾衰竭和死亡。导致肾衰竭的关键事件是由足细胞的丧失。这是肾脏疾病称为局灶性节段的原因肾小球硬化（FSGS）。尽管肾脏疾病的患病率越来越大目前尚无FDA批准的疗法，以防止足细胞损失。这笔赠款的目标应用是为了深入了解足细胞所涉及的分子机制与BRAF信号通路相关的伤害，因此可以针对治疗益处。我们从由称为PDSS2的酶突变引起的罕见的遗传肾脏疾病。有趣的是，我们发现该酶的功能丧失会导致足细胞死亡，从而导致在FSG中。随后，我们发现预防足细胞死亡的关键分子是BRAF，一种激活BRAF的小分子，称为GDC-0879，可以保护足细胞免受细胞死亡的影响。实际上，GDC-0879能够保护足细胞免受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保护足细胞损伤的小鼠和由此产生的肾脏过滤器损伤（称为蛋白尿）。在这里，我们会的探索与BRAF相关的足细胞损伤有关的精确分子机制，并 GDC-0879的潜力成为FSG的治疗方法。成功完成这项工作可能会为FSG和慢性肾脏疾病，可能很容易带到诊所，因为GDC-0879是 FDA已经批准了其他适应症的药物。