Role of AMP-kinase pathway in the regulation of Minimal change disease-to-FSGS transition

AMP-激酶途径在微小病变向 FSGS 转变调节中的作用

• 批准号: 10585051
• 负责人: Madhav C Menon
• 金额: $ 55.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585051
• 关键词: 1 year old; Actins; Adriamycin PFS; Albuminuria; Autophagocytosis; Biological Models; Biopsy; Case Series; Case Study; Cell Survival; Cytoplasm; Cytoskeleton; Data; Diagnostic; Diagnostic Procedure; Diffuse; Dimensions; Disease; End stage renal failure; Event; FDA approved; FYN gene; Focal and Segmental Glomerulosclerosis; Foot Process; Genetic; Genetic Models; Growth; Human; Hypertrophy; In Vitro; Injury; Investigation; Kidney Failure; Mediating; Modeling; Morphology; Multiple Trauma; Mus; Nephrectomy; Nephrotic Syndrome; Pathology; Pathway interactions; Phenotype; Phosphotransferases; Proteinuria; Proteomics; Proto-Oncogene Proteins c-fyn; Regulation; Role; STK11 gene; Signal Transduction; Stress; Technology; Testing; Therapeutic; Toxin; Visualization; Work; adenylate kinase; aged; biobank; cohort; design; glomerulosclerosis; in vitro Model; in vivo; inhibition of autophagy; injured; innovation; knock-down; morphometry; novel; novel therapeutics; overexpression; pharmacologic; podocyte; preservation; prevent; prognostic value; protective effect; response; self-renewal; transcriptomics

Project Summary: Nephrotic syndrome (NS) is characterized by proteinuria and is associated with podocyte actin cytoskeletal disorganization termed foot process effacement (FPE). Podocytes are incapable of self- renewal, and podocyte loss above~40% per glomerulus associates with glomerulosclerosis (FSGS) and kidney failure. Distinct from FSGS, Minimal Change Disease (MCD) also shows diffuse FPE, but has preserved podocyte numbers, and is highly treatment responsive with a low rate of progression to ESRD (5-20% in 20 years). FSGS has been associated with glomerulomegaly and podocyte hypertrophy in later stages. However, early FSGS can be morphologically indistinguishable from MCD and a debate exists whether some MCD cases transition to FSGS, representing a “switch” between diseases. Hence, understanding signals specific to MCD will reveal mechanisms facilitating podocyte survival and preventing a phenotype “switch”. Interestingly, Fyn kinase inactivation was specifically identified in human MCD. In mice, Fyn inactivation (by Shroom3 silencing) also associated with FPE without podocytopenia - an “MCD-like” pathology. Hence Fyn inactivation was a candidate MCD-unique signal. Downstream of Fyn-inactivation, investigation of anti-hypertrophy and pro- survival pathways in podocytes revealed enhanced activation of AMP-kinase, explaining these effects. Fyn inactivation activated AMPK by increasing cytoplasmic efflux of LKB1. Moreover, inhibition of Ampk in MCD-like mice induced podocyte loss, glomerulomegaly and FSGS, while AMPK activation prevented podocyte loss after glomerular injury induced by hypertrophy and direct toxins. Invitro data show increased autophagy as the central pro-survival mechanism in podocytes after AMPK-activation. We hypothesize that in the context of injury causing podocyte FPE, AMPK signaling regulates the “switch” between MCD and FSGS by enhancing autophagy and preventing podocytopenia. In this proposal, we will test the role of podocyte AMPK signaling in MCD vs FSGS, and establish downstream mechanisms regulating podocyte survival. In Aim I, we will use genetic and pharmacologic model systems to specifically inactivate or activate AMPK to induce phenotype changes from MCD-to-FSGS and vice versa. In Aim-II, we will modulate autophagy in podocytes while activating AMPK to show the central role of AMPK-mediated autophagy in podocyte survival. We will also specifically examine the role of autophagy in restricting glomerulomegaly during injury. Finally, in Aim-III, applying state-of-the-art and multidimensional technologies to the largest NS cohort in the US, we will investigate the specific role of AMPK signaling in human MCD vs FSGS. Our work will provide novel MCD-FSGS diagnostics, and develop novel AMPK therapeutics as well as help repurpose FDA-approved AMP-activators.

项目概述：肾病综合征（NS）以蛋白尿为特征，与足细胞相关