The significant positive correlation between basal stress hormones and glucose and cholesterol in the C57BL/6 and L-PGDS KO mice confirms the hypothesized connection between diet-induced hyperglycemia and hypercholesterolemia and hyper-activity of the hypothalamic-pituitary adrenal axis. As expected, the LPGDS KO mice experience the high-fat diet-induced increase in HPA activity earlier than controls. These data support the initial hypothesis. Unexpectedly the L-PGDS KO mice are resistant to an increase in ACTH levels with age which points to a role for prostaglandin D2 synthase in age-related and long-term high-fat feeding related changes of the HPA axis. The additional novel data showing reduced bone size and reduced bone formation parameters in L-PGDS KO mice indicate that PGD2 plays an anabolic role during bone formation. We have established the expression pattern of MC-R in aorta-derived mesenchymal progenitors as well as rat bone marrow derived mesenchymal progenitors which will prove invaluable for the continued success of this project. The ACTH-evoked calcium mobilization via the MC2-R observed in these mesenchymal progenitor cell lines provides the mechanism through which ACTH initiates chondrogenic differentiation. The nature of the calcium flux in response to ACTH also appears to be dependent on lineage differentiation potential in aortic MSC populations as well as bone-marrow derived mesenchymal progenitors. These data provide new insight into mesenchymal cell calcium" handling during lineage commitment. The data providing evidence of locally produced and processed POMC derived peptides and the regulation by dexamethasone also, opens a new avenue of research;one that encompasses the interactions between leukocytes and mesenchymal progenitors during inflammatory processes. Overall data from the training period confirm the original hypothesis that mesenchymal cells in the aorta and bone marrow can respond to ACTH with changes in intracellular calcium that can ultimately result in their transition to the calcifying chondrogenic/osteogenic lineage and provide the foundation for further studies investigating this pathway in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL091116-04
Application #
8532956
Study Section
Special Emphasis Panel (NSS)
Program Officer
Olive, Michelle
Project Start
2009-09-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$237,048
Indirect Cost
$54,213
Name
Winthrop-University Hospital
Department
Type
DUNS #
065937856
City
Mineola
State
NY
Country
United States
Zip Code
11501