权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10408161
负责人：
Anna Greka
金额：
$ 40.77万
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 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408161
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 Persons 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.

摘要慢性肾脏疾病影响着全球超过7亿人，是一种常见的病因肾功能衰竭和死亡。导致肾衰竭的一个关键事件是滤过器损伤，由足细胞丢失。这是一种称为局灶性节段性肾病的原因。肾小球硬化(FSGS)。尽管肾脏疾病的发病率不断上升，但仍有目前还没有FDA批准的治疗方法来防止足细胞丢失。这笔赠款的目的是应用是为了深入了解足细胞所涉及的分子机制与BRAF信号通路相关的损伤，因此它可能成为治疗的靶点。我们从一种罕见的遗传性肾脏疾病开始，这种疾病是由一种名为PDSS2的酶的突变引起的。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。我们随后发现，防止足细胞死亡的一个关键分子是BRAF和一种激活BRAF的小分子，称为GDC-0879，可以保护足细胞免受细胞死亡的影响。事实上，GDC-0879能够保护足细胞免受几种损伤，包括有毒的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可以保护小鼠的足细胞损伤和由此引起的肾脏滤器损伤(称为蛋白尿)。在这里，我们将探讨BRAF相关足细胞损伤的确切分子机制，以及 GDC-0879有可能成为治疗FSGS的药物。这项工作的成功完成可能会为FSGS和FSGS提供一种新的、急需的治疗方法慢性肾脏疾病，也是一种很容易带到临床的疾病，因为GDC-0879是 FDA已经批准了用于其他适应症的药物。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies.

钙，TRPC通道和足细胞中肌动蛋白细胞骨架的调节：迈向靶向疗法的未来。

DOI：
10.1007/s00467-015-3224-1
发表时间：
2016-07
期刊：
Pediatric nephrology (Berlin, Germany)
影响因子：
0
作者：
Wieder N;Greka A
通讯作者：
Greka A

SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity.

DOI：
10.1186/1471-2121-13-33
发表时间：
2012-11-21
期刊：
BMC cell biology
影响因子：
0
作者：
Carrasquillo R;Tian D;Krishna S;Pollak MR;Greka A;Schlöndorff J
通讯作者：
Schlöndorff J

N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer's disease mouse model.

DOI：
10.1038/s41467-023-36759-8
发表时间：
2023-03-09
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Suzzi, Stefano;Croese, Tommaso;Ravid, Adi;Gold, Or;Clark, Abbe R.;Medina, Sedi;Kitsberg, Daniel;Adam, Miriam;Vernon, Katherine A.;Kohnert, Eva;Shapira, Inbar;Malitsky, Sergey;Itkin, Maxim;Brandis, Alexander;Mehlman, Tevie;Salame, Tomer M.;Colaiuta, Sarah P.;Cahalon, Liora;Slyper, Michal;Greka, Anna;Habib, Naomi;Schwartz, Michal
通讯作者：
Schwartz, Michal

Randomized Clinical Trial Design to Assess Abatacept in Resistant Nephrotic Syndrome.

DOI：
10.1016/j.ekir.2017.08.013
发表时间：
2018-01
期刊：
Kidney international reports
影响因子：
6
作者：
Trachtman H;Gipson DS;Somers M;Spino C;Adler S;Holzman L;Kopp JB;Sedor J;Overfield S;Elegbe A;Maldonado M;Greka A
通讯作者：
Greka A

Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity.