Karam Aboudehen, PhD
Assistant Professor of Medicine
Division of Nephrology & Hypertension
Department of Medicine
Renaissance School of Medicine
101 Nicolls Rd, HSC T 15-103
Stony Brook University
karam.aboudehen@stonybrookmedicine.edu
lncRNA in PKD
Research Focus
Polycystic kidney disease (PKD) is a debilitating genetic disorder characterized by the accumulation of massive bilateral cysts in the kidneys, which leads to end stage renal disease (ESRD). The pathophysiology of PKD is incompletely understood, and treatment options are limited. We study long noncoding RNA (lncRNA) in the pathogenesis of PKD. LncRNAs are a class of non-protein coding RNAs that have pivotal functions in development and disease. They have emerged as an exciting new drug target category for many common conditions. However, the role of lncRNAs in PKD is not known.
Our long-term objective is to discover therapeutically targetable lncRNAs that prevent or mitigate cyst formation and/or progression in PKD. We have utilized multiple orthologous PKD mouse models and identified lncRNAs that are dysregulated during cystogenesis. We performed specific gene targeting approaches and identified several lncRNAs, such as Hoxb3os and Pvt1, that directly modulate cystogenesis. Our early findings reveal that downregulation of lnc-Hoxb3os exacerbates cystogenesis in murine PKD, whereas upregulation of lnc-Pvt1 is deleterious in driving cyst progression. Preliminary mechanistic studies indicate that Hoxb3os alleviates cystogenesis by antagonizing mTOR signaling and regulating cellular metabolism, whereas Pvt1 upregulation exacerbates cystogenesis by stabilizing c-MYC levels.
We are addressing several important questions that could provide a rationale for future potential therapeutic approaches. For example, how do Pvt1 and Hoxb3os bind to specific protein targets, and can this binding be pharmacologically targeted? Can we develop Pvt1 inhibitors in vivo using LNA/GapmeRs and/or antisense oligos? Can we stabilize Hoxb3os expression in kidney using viral gene delivery?
Cutting-edge technologies we currently utilize include:
· Mouse molecular genetics
· Next generation sequencing and mass spectrometry
· Immunohistochemistry in situ hybridization
· Genetic engineering using CRISPR/Cas9
· RNA pulldown using ChIRP assays
· Viral gene delivery in ex-vivo kidney culture
· Cell culture and molecular cloning technology
Grant Support:
Current:
1- K01DK116934-02 Aboudehen (PI) 5/15/19–5/31/24 NIH/NIDDK
Deregulation of Noncoding RNA in the Pathogenesis of Autosomal Dominant Polycystic Kidney Disease
2- R01DK42921: Igarashi (PI and mentor), Aboudehen (Co-PI) 06/30/2021–08/16/2026 The major goals of this NIH MERIT Award are to understand the roles of HNF-1β in kidney development, kidney-specific gene expression, and cystic kidney disease.
Previous Research Support:
- REG-217886-01 Aboudehen (PI) 5/30/2018-6/30/2020 Mayo clinic-Rochester
Long noncoding RNA Hoxb3os is dysregulated in ADPKD and regulates mTOR signaling
Publications
Recent Publications:
1. Eckberg K, Weisser I, Buttram D, Somia N, Igarashi P, Aboudehen K: Small hairpin inhibitory RNA delivery in the metanephric organ culture identifies long noncoding RNA Pvt1 as a modulator of cyst growth. Am J Physiol Renal Physiol, 323: F335-F348, 2022 10.1152/ajprenal.00016.2022
2. Lakhia R, Yheskel M, Flaten A, Ramalingam H, Aboudehen K, Ferre S, et al.: Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression. JCI Insight, 5, 2020 10.1172/jci.insight.133785
3. Aboudehen K: Regulation of mTOR signaling by long non-coding RNA. Biochim Biophys Acta Gene Regul Mech, 1863: 194449, 2020 10.1016/j.bbagrm.2019.194449
4. Chan SC, Zhang Y, Shao A, Avdulov S, Herrera J, Aboudehen K, et al.: Mechanism of Fibrosis in HNF1B-Related Autosomal Dominant Tubulointerstitial Kidney Disease. J Am Soc Nephrol, 29: 2493-2509, 2018 10.1681/ASN.2018040437
5. Aboudehen K, Farahani S, Kanchwala M, Chan SC, Avdulov S, Mickelson A, et al.: Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling. J Biol Chem, 293: 9388-9398, 2018 10.1074/jbc.RA118.001723
