Abstract
| Grant Number: | 5R44HL074699-03 |
| Project Title: | ER beta selective agonist coronary protection-menopause |
Abstract: DESCRIPTION (provided by applicant): This Phase II project continues with studies of rhesus monkeys in vivo to further test, and develop toward approval as a drug for human use, a novel estrogen receptor beta (ERbeta or ERb) selective (over ERalpha or ERa) agonist that is hypothesized to be effective for maintaining function of coronary arteries and also for relieving vasomotor symptoms of steroid deficiency and hormonal imbalance. The new drug will be formulated with the aim of protection of coronary arteries against hyperreactivity as a proactive step to reduce the incidence of coronary dysfunction in both women and men. The designated indication, to reduce coronary hyperreactivity, is hypothesized to result from deficiencies in steroid hormones and the imbalance of ERbeta/ERalpha stimulation that develops with hypogonadal function, menopause, and in the normal aging process. Dimera in vivo cardiac catheterization and in vitro primary VMC (vascular muscle cell) cultures have pioneered tests for effectiveness in preventing hyperreactivity. PanVera ERbeta fluorescence polarization analysis adds genomic regulation dimensions to the plan. The newly discovered endogenous ERbeta Agonist (ErbetaA or ERbA) will be studied in adult female and male rhesus (Macaca mulatta) in the catheterization laboratory, and in VMC isolated from rhesus coronary arteries. The effectiveness of the new ERbetaA in preventing coronary hyperreactivity will be assessed by an established protocol based on responses to vasoconstrictor challenges during angiography. Tissue Factor Pathway Inhibitor (TFPI) levels will be measured as an index of protection against thromboembolism. In addition, C-Reactive Protein (CRP) in serum and thromboxane B2 in urine will be used as adverse indicators. Histopathology and Ki67 immunocytochemistry will be included to determine whether there are effects of the ERbetaA on breast or uterine (or prostate in males) cell proliferation. Isolated coronary vascular muscle cells will be studied to investigate receptor roles in related protective actions on Ca 2+and PKC signals. The new ERbetaA is to be contrasted with PremPro(r) (oral conjugated equine estrogens plus medroxyprogesterone acetate) which failed to provide cardiovascular protection in the Women's Health Initiative.
Thesaurus Terms:
androstane compound, chemoprevention, coronary disorder, drug screening /evaluation, estrogen receptor, heart disorder chemotherapy, nonhuman therapy evaluation, postmenopause, stimulant /agonist
angiography, calcium ion, cardiac myocyte, coronary artery, human mortality, thromboembolism, thromboxane, topical drug application, vasoconstrictor
Macaca mulatta, animal tissue, immunocytochemistry
| Institution: | DIMERA, INC. |
| SUITE 311 |
| PORTLAND, OR 97210 |
| Fiscal Year: | 2005 |
| Department: | |
| Project Start: | 07-JUL-2003 |
| Project End: | 31-MAR-2008 |
| ICD: | NATIONAL HEART, LUNG, AND BLOOD INSTITUTE |
| IRG: | ZRG1 |
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