Physiological roles of nuclear PLTP

University Of Washington, Seattle WA

Investigators

Abstract

Phospholipid transfer protein (PLTP) is involved in transfer of fats in the blood to and from the cells. To perform these well-known functions, PLTP is required to be present only on the outside of the cell, in the so-called extracellular space. Surprisingly, recent studies have shown that PLTP is also present in the nucleus, which is a part of the cell that regulates expression of cell proteins and how the cell functions. However, at this time, nothing is known about how PLTP functions inside the nucleus. This application proposes to establish a new paradigm that PLTP transfers fats from the outside of the cell into the nucleus, and by doing so regulates intranuclear functions that are important for normal cell functioning. Furthermore, recent studies have shown that PLTP itself, unrelated to its fat transfer functions, is involved in regulation of processes in the cell. Therefore, the application proposes to test how and by which mechanism PLTP affects intranuclear processes that regulate expression of proteins, and how parts of PLTP?s genetic code modulate fate of the cell. To achieve these goals, the PLTP molecule will be changed, creating PLTP mutants that lack specific properties, such as ability to transfer fats, enter the nucleus or bind to its intranuclear targets. These studies will test the functions related to transfer of fats to the nucleus and binding to DNA (genetic code in the nucleus). The proposed studies address significant basic research questions that have not been previously evaluated, but are critical to better understanding of both normal and abnormal cellular functioning. The new ideas that will be tested in this project have great potential to change thinking about regulation of cellular function, which would have an impact on nearly all aspects of cell biology. Furthermore, normal PLTP levels and activity appear to be of great importance, but relative lack of knowledge of its functions at the cellular level currently prevents further development of models and methods that would harness its functional properties to prevent or treat chronic human disorders and diseases, including cancer, diabetes and Alzheimer?s disease. Without clear understanding of PLTP?s normal functions, particularly those related to the nucleus, it would be impossible to understand how defects in PLTP functions cause disease. Therefore, the proposed studies will form an important foundation for advancement of science in general, and for improvement and development of new approaches to prevention and treatment of human diseases.