The long-term objective of this research proposal is to investigate how metabolic regulators affect lymphocyte survival. Regulation of cell survival is important in maintaining the homeostasis of the hematopoietic system and failure of cells to die plays a role in the pathogenesis of chronic leukemias and indolent lymphomas. Recent investigations in Dr. Thompson's laboratory have demonstrated that perturbation in metabolic pathways upstream of mitochondrial electron transport leads to loss of mitochondria integrity, cytochrome c release and cell death. BCI-XL, an antiapoptotic protein of the Bcl-2 family, maintains mitochondrial homeostasis by promoting efficient ADP-coupled oxidative phosphorylation under conditions of substrate limitation. In light of these findings, we hypothesize that factors affecting cellular metabolic activities may have impacts on cell survival. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been chosen to test our hypothesis because of its role in metabolic regulation. PPARgamma is a nuclear hormone receptor/transcriptional factor. Upon ligand binding, it activates target genes involved in fatty acid and triglyceride synthesis in adipose tissue. Recent studies have shown that PPARgamma is also expressed in T lymphocytes and it may play a role in immunomodulation. We have demonstrated that treatment of murine lymphocytes with 15d-PGJ2 and ciglitazone, ligands of PPARy, selectively induce death of B and T cells. Furthermore, we have shown that the PPARgamma ligand-induced lymphocyte death is not prevented by BCI-XL. These findings suggest that PPARgamma ligands are potentially useful for the treatment of lymphomas overexpressing Bcl-2, such as follicular lymphomas. We seek to determine the molecular and metabolic mechanisms of PPARygamma ligand-induced death.
The specific aims of this proposal are: 1) To determine whether death induced by l5d-PGJ2 and ciglitazone is mediated through PPARgamma using established hematopoietic cell lines and primary lymphocytes; 2) To determine the effects of PPARgamma ligands on known apoptotic and survival pathways, and cellular metabolism; 3) Identify genes that are induced by PPARgamma activation in hematopoietic cells using gene expression microarray technology. Understanding the mechanisms that regulate the metabolism of hernatopoietic cells may lead to the development of novel therapeutic strategies for hematologic disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08HL068850-02
Application #
6620873
Study Section
Special Emphasis Panel (ZHL1-CSR-M (O1))
Program Officer
Werner, Ellen
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$130,680
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065