Cardiometabolic Research

BRITE researchers are investigating the effects of thyroid hormone on Alzheimer’s disease and cancer. Alzheimer’s disease is a progressive neurodegenerative disorder that currently affects more than 18 million individuals worldwide. Among the risk factors that have been described for this disease is hypothyroidism, the second most common endocrine disorder in America. Thyroid hormone plays a key role in the development and maintenance of basal forebrain cholinergic neurons typically involved in Alzheimer’s disease. Furthermore, in vitro studies have shown that thyroid hormone regulates the expression of the APP gene, the precursor of A?, and the splicing of Tau protein at exon 10. Our goal is to determine whether there is a direct relationship between hypothyroidism and the appearance of Alzheimer’s disease markers. 

Breast cancer is the most common cancer among women and the second leading cause of cancer deaths in women after lung cancer. Extensive research is currently underway to identify agents that could induce apoptosis in breast cancer cells facilitating therapeutic intervention and potentially improve outcomes for breast cancer patients. A hormone that could be useful in the induction of apoptosis in breast cancer cells is thyroid hormone. Hypothyroidism and low-normal free thyroxine are related to an increased risk of breast cancer in post-menopausal women and with a reduction in the response to treatment. In this project, we are concentrating in determining the mechanisms involved in the control of breast cancer cell proliferation by thyroid hormone. 

BRITE researchers are investigating the regulation of the hepatic low-density lipoprotein (LDL) receptor and PCSK9. High levels of LDL are well known to be associated with an increased risk for atherosclerosis. The key atherogenic property of LDL particles involves the formation of atherosclerotic plaque. Since the hepatic LDL receptor is the major determinant of plasma LDL-cholesterol levels, direct regulation of the LDL receptor gene by factors such as cholesterol biosynthesis inhibitors, currently used to treat hypercholesterolemia, and hormones such as thyroid hormone and insulin is expected. PCSK9 is a convertase that controls the protein expression of the hepatic LDL receptor. The goal of our research is to characterize the molecular mechanisms involved in the regulation of the LDL receptor and PCSK9 genes. 

Heart disease ends the life of more people than any other disease in the United States. High levels of LDL-cholesterol cause heart diseases by increasing the formation of atherosclerotic plaques. BRITE researchers are investigating the role that PCSK9 plays in indirectly regulating LDL levels, modulating glucose intolerance, insulin resistance, abdominal obesity, inflammation, and hypertension. The magnitude of PCSK9's involvement in the onset of these metabolic abnormalities appears to be associated with age, sex, and ethnic background. Another regulator, the inducible degrader of the LDL receptor (IDOL), works by enhancing the ubiquitination of the LDL receptor. At BRITE, we are reviewing the functions and regulatory mechanisms of PCSK9, the effects of PCSK9 on the LDL receptor, the relationship of this convertase with IDOL, and treatments currently available against hypercholesterolemia.