Chloride is the most abundant free anion in animal cells. It's not surprising that chloride channels are involved in a wide range of functions as diverse as cell volume regulation, epithelial fluid secretion, regulation of electrical excitability, and acidification of intracellular organelles. Their physiological function is impressively illustrated by many diseases (channelopathies) caused by chloride channel mutations, such as cystic fibrosis (1 in 2,000 Caucasians), myotonia, kidney stones, and osteopetrosis. However, despite recent progress, chloride channels are considerably under-studied compared to their cation (sodium, potassium, and calcium) channel cousins. Many electrophysiologically well characterized chloride channels still lack molecular identity. Several factors block progress in this field. Unlike cation channels, there are no sequence homologies (for example, conserved pore-lining motif) among known chloride channel families. The lack of specific high-affinity channel ligands (e.g. toxins) hinders direct purification. Expression cloning, an otherwise powerful technique, is hampered by high endogenous expression of channel channels in popular expression systems. The absence of molecular identity presents the biggest roadblock to elucidate the precise biological function of these widely expressed pore-forming membrane proteins. The proposed research program will combine increasingly powerful genomics tools (including bioinformatics, proteomics and gene manipulation) with electrophysiology and imaging techniques to identify novel chloride channels and investigate their physiological function using mouse models. Our results will shed light on the molecular identity and function of new chloride channels and may provide therapeutic strategies to target them for diseases with abnormal chloride transport and homeostasis.

Public Health Relevance

Chloride channels play important functions in human health and disease. Their mutations cause many genetic disorders (channelopathies), such as cystic fibrosis (1 in 2,000 Caucasians), myotonia, kidney stones, and Bartter's syndrome . This study will elucidate the molecular identity and the physiology role of novel chloride channels.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM124824-03
Application #
9746742
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nie, Zhongzhen
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Osei-Owusu, James; Yang, Junhua; Vitery, Maria Del Carmen et al. (2018) Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC). Curr Top Membr 81:177-203