The sodium-potassium-chloride-cotransporter (NKCC) family of transporters are critical to the reabsorption of ions in the kidney and other parts of the body. As a member of the larger solute carrier 12 (SLC12A) family, these transporters move sodium, potassium, and chloride across the cell membrane in order to maintain ionic homeostasis and regulate blood pressure. As a result of their important roles in physiology, they are also among the most widely targeted transporters in medicine. Drugs such as the loop diuretics and thiazide diuretics have been in use for decades, and are fundamental medications to treating conditions such as edema, cirrhosis, heart failure, and hypertension. Yet despite their widespread use, little is known about the molecular mechanism by which they operate. This project will address that gap in knowledge, by studying the NKCC group of transporters from a fundamental, basic science perspective. An in vitro functional assay will be developed in order to study the transport mechanism of NKCC in a well-defined system. Key components responsible for ion recognition and binding, as well as inhibitor binding sites will be determined using mutagenesis coupled with functional assays. The above knowledge will be combined with structural characterizations about NKCC to understand its function. As a whole, this study will reveal the fundamental mechanisms about how NKCC transporters operate and how they are targeted. This information will lead to better pharmaceuticals, with fewer side effects.

Public Health Relevance

The NKCC family of proteins is the drug target for some of the most widely prescribed medications, for illnesses ranging from nephrotic syndrome and cirrhosis to hypertension and heart failure. But despite decades of clinical use, the molecular mechanisms of protein-drug interactions remains unclear. This project will elucidate the mechanism behind ion transport and drug interactions within the NKCC family, potentially leading to the design of better medications with fewer side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK114983-03
Application #
9767115
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Maric-Bilkan, Christine
Project Start
2017-09-15
Project End
2021-12-14
Budget Start
2019-09-15
Budget End
2020-09-14
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305