DNA damage response pathways in podocytes: novel targets to treat focal segmental glomerulosclerosis

足细胞 DNA 损伤反应途径：治疗局灶节段性肾小球硬化症的新靶点

• 批准号: 398497730
• 负责人: Professorin Dr. Christine Kurschat
• 金额: --
• 依托单位: Institute for Genome Stability in Ageing and Disease
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398497730?language=en
• 关键词: DNA; damage; response; pathways; podocytes

Accumulating DNA damage and alterations in DNA damage response signaling play fundamental roles in the aging process and contribute to a wide range of aging-associated diseases. For terminally differentiated glomerular podocytes functional maintenance including the continuous repair of their genome is of great importance for cellular survival. Accordingly, we recently identified the progeria-associated gene Ercc1, coding for a key enzyme in DNA nucleotide excision repair (NER), to counteract glomerular aging. Genome-wide transcriptome analyses revealed the signature of aged glomeruli in 14 week-old compound heterozygous mice harboring a loss-of-function and a hypomorphic allele of Ercc1 (Ercc1-/Δ). Subsequently, we have generated a podocyte-specific Ercc1 knockout mouse model (Ercc1pko). These mice display severe podocyte dysfunction and histologic evidence of focal segmental glomerulosclerosis (FSGS). Based on our previous data we hypothesize that accumulation of DNA damage in podocytes plays a fundamental role in the development of FSGS in the elderly. The overarching goal of this proposal is to understand the mechanisms how DNA damage response (DDR) signaling affects podocyte homeostasis and survival and how alterations of this network lead to FSGS. Specifically, we aim (1) at delineating the crosstalk between DNA damage signaling and known pathways crucial for podocyte homeostasis using mouse models and C. elegans, (2) at unraveling the impact of DDR signaling and DDR preconditioning in experimental mouse models of FSGS, and (3) at investigating the role of mTOR inhibition, caloric restriction and cellular senescence in DDR-related FSGS. We expect that this project will significantly enhance the understanding of age-related FSGS and lead to the identification of novel targets potentially amenable to pharmacological interventions.

累积的DNA损伤和DNA损伤反应信号的改变在衰老过程中起着重要作用，并导致广泛的衰老相关疾病。对于终末分化的肾小球足细胞，功能维持包括其基因组的持续修复对于细胞存活非常重要。因此，我们最近确定了早老症相关基因Ercc 1，编码DNA核苷酸切除修复（NER）中的关键酶，以对抗肾小球衰老。全基因组转录组分析揭示了14周龄复合杂合子小鼠中老年肾小球的特征，该小鼠具有Ercc 1的功能丧失和亚型等位基因（Ercc 1-/Δ）。随后，我们建立了足细胞特异性Ercc 1基因敲除小鼠模型（Ercc 1 pko）。这些小鼠表现出严重的足细胞功能障碍和局灶节段性肾小球硬化症（FSGS）的组织学证据。根据我们以前的数据，我们假设足细胞中DNA损伤的积累在老年人FSGS的发展中起着重要作用。该提案的总体目标是了解DNA损伤反应（DDR）信号传导如何影响足细胞稳态和存活的机制，以及该网络的改变如何导致FSGS。具体来说，我们的目标是（1）使用小鼠模型和C. elegans，（2）在FSGS的实验小鼠模型中解开DDR信号传导和DDR预处理的影响，和（3）在研究mTOR抑制，热量限制和细胞衰老在DDR相关的FSGS中的作用。我们期望该项目将显著增强对年龄相关FSGS的理解，并导致识别可能适合于药物干预的新靶点。