From target to modulator: integrative approaches to understanding and activating the gamma-glutamyl cycle in heart failure
From target to modulator: integrative approaches to understanding and activating the gamma-glutamyl cycle in heart failure
Heart failure is a disease in which the heart can no longer pump blood well enough for the body. Many treatments already exist, but many patients still become seriously ill. One possible reason is that heart failure also affects what happens inside cells. Cells can lose part of their natural protection against damage.
This thesis of Jose Esquivel Gaytan studies one of these protective systems: the gamma-glutamyl cycle. The main result is that we found a way to increase the activity of OPLAH, a protein in this cycle. To do this, we first had to make the protein in the laboratory, purify it, and develop a test to measure whether it was working. We then screened different compounds and found that 5-AMP, a molecule already present in the body, can make OPLAH more active. Since 5-AMP does not easily enter cells, we also developed small particles to help carry it inside.
The thesis also studies 5-oxoproline, a small molecule from the same cycle. In patients with heart failure, higher levels of 5-oxoproline in the blood were linked to worse outcomes and to signals involving both the heart and the kidneys. One of the related signals was TGF-alpha. The thesis also shows that glutathione, one of the body’s important protective substances, is often lower in heart failure.
Finally, the thesis looks at whether heart failure should be understood only by how well the heart pumps. By measuring many molecules at once, we may see hidden differences between patients who seem similar in the clinic.