Valeriu Cebotaru, MD, is an Instructor in the Division of Nephrology at Johns Hopkins University. He seeks a Mentored Basic Science-Oriented Research Career Development Award in order to obtain essential skills and mentored research experience for an independent career as a physician scientist in the field of polycystic kidney disease. The research proposal details a five-year plan consisting of coursework in Molecular Medicine, Statistics and Epidemiology, mentorship by Dr. William Guggino, PhD and basic science research training in molecular biology and biochemistry with primary focus on autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a hereditary disorder that affects 1:1000 to 1:500 people and is characterized by fluid-filled cysts that arise from renal tubules. ADPKD results from mutations in either the PKD1 or PKD2 gene, which encode the gene products polycystin 1 (PC1) and polycystin 2 (PC2), respectively. Although PC1 and PC2 have been studied intensively, information on how they function to promote tubulogenesis or how a malfunction of either protein leads to cyst formation is still emerging. Histone deacetylase 6 (HDAC6) expression and activity are increased in Pkd1 mutant renal epithelial cells, and we have found that HDAC6 levels are increased in Pkd2 knockout MEF cells, suggesting that an intact PC1-PC2 complex is required to regulate HDAC6. In PKD, the cystic epithelium has an increased proliferative index; interestingly, overexpression of HDAC6 promotes anchorage-independent proliferation, whereas knockdown of HDAC6 inhibits anchorage-independent proliferation in cancer cell lines. We propose a novel concept in which disruption of the PC1-PC2 complex as a result of mutations in the PKD1 or PKD2 gene leads to increased HDAC6 levels/activity and subsequent cyst formation; targeting HDAC6 activity could prevent cyst formation or perhaps slow down cyst growth.
The specific aims of the research agenda are to: 1) To determine the role of the PC1, PC2, and HDAC6 interrelationship in cyst formation. The overall hypothesis of this Aim is that in the absence of PC1 or PC2, increased HDAC6 activity will promote cyst formation. 2) To assess the impact of HDAC6 binding to PC2. The overall hypothesis of this Aim is that aberrant degradation and trafficking of PC2 is regulated by HDAC6 and by additional signal transduction systems regulated by PC1. 3) To define the role of HDAC6 in tubule function. The overall hypothesis of this Aim is that increased activity of HDAC6 will lead to aberrant calcium signaling and cell polarity in ADPKD, two critical epithelial functions that are dysregulated in ADPKD. Currently, there is no cure for ADPKD. One promising therapy involves the vasopressin V2 receptor antagonist, which inhibits cyst development in animal models of ADPKD and has been tested in humans but has not yet been approved as a therapy. However, given the multitude of pathways mis-regulated in ADPKD, a combination therapy that targets different pathways may be more efficacious. Our hypothesis is that disruption of the PC1-PC2 complex as a result of mutations in the PKD1 or PKD2 gene will lead to increased HDAC6 level/activity and could subsequently lead to cyst formation; targeting HDAC6 activity could prevent cyst formation or perhaps slow down cyst growth. This pre-translational proposal will study how the PC1-PC2 complex regulates cyst formation through HDAC6 in both 3D culture and animal models of PKD. HDAC6 inhibitors are being tested intensively in the treatment of various malignancies and could be considered as an ADPKD treatment in the future.

Public Health Relevance

This proposal will study a unifying concept of how cysts form in Autosomal Dominant Polycystic Kidney Disease. It will also provide novel insights into how to prevent or slow down cyst growth which could potentially lead to a new therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK103078-03
Application #
8917215
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2014-09-01
Project End
2019-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
$147,042
Indirect Cost
$10,892
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cebotaru, Liudmila; Liu, Qiangni; Yanda, Murali K et al. (2016) Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney Int 90:90-9