TTP as a Regulator of GM-CSF mRNA Deadenylation and Stability


The disclosed invention provides materials and methods to treat granulocytopenia (low white cell count in the blood) which is characterized by a reduced number of granulocytes (relative) or an absence of granulocytes (absolute). This condition is commonly associated with cancer chemotherapy, but is seen less frequently in a number of conditions including the use of propylthiouracil, radiotherapy for marrow ablation for bone marrow transplantation, aplastic anemia, systemic lupus erythematosus, AIDS and a variety of other situations. The invention proposes a method to increase GM-CSF levels in a treated subject, and this increase is achieved by inhibiting the degradation of GM-CSF messenger RNA (mRNA). Tristetraprolin (TTP) is one member of a family of cys-cys-cys-his (CCCH) zinc finger proteins, and it is a factor that binds to and causes the instability of GM-CSF mRNA. Methods are provided for the development of screening assays for molecules that inhibit the binding of TTP and its related proteins to GM-CSF mRNA, or otherwise inhibit the effect of TTP to promote breakdown of the mRNA, leading in turn to increased mRNA stability and enhanced production of GM-CSF. Compounds identified by such screens, and their derivatives, could be useful in treating granulocytopenia from whatever cause.

Inventors:

Ester Carballo (NIEHS)  ➽ more inventions...

Wi Lai (NIEHS)  ➽ more inventions...

Perry Blackshear (NIEHS)  ➽ more inventions...


Intellectual Property:
PCT Pat: 7,238,473 issued 2007-07-03
US Application No. 10/049,586 filed on 2002-02-12
US Application No. 60/148,810 filed on 1999-08-13

Publications:
Carballo E, Lai WS, Blackshear PJ. Evidence that tristetraprolin (TTP) is a physiological regulator of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA deadenylation and stability. Blood 2000 Mar 15;95(6):1891-1899. PubMed abs
Lai WS, Carballo E, Thorn JM, Kennington EA, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA. J Biol Chem. 2000 Jun 9;275(23):17827-17837. PubMed abs

Licensing Contact:
Vidita Choudhry, Ph.D.
Email: vidita.choudhry@nih.gov
Phone: 301-594-4095

OTT Reference No: E-204-1999-0
Updated: Jun 3, 2010