As a matrix biologist, vascular biologist, and geneticist, Dr. Kozel seeks to better understand the factors that influence vascular disease severity in patients with rare connective tissue disorders. The majority of Dr. Kozel’s work is focused on the study of two elastin insufficiency-related diseases: the neurodevelopmental condition known as Williams syndrome (WS) and isolated supravalvular aortic stenosis (SVAS), a narrowing of the aorta, the vessel that carries blood from the heart to the rest of the body.
As its name implies, elastin is an elastic protein — it helps blood vessels as well as other tissues in the body stretch and recoil. Individuals with WS are missing one copy of 26 to 28 genes, including the elastin gene — usually there are two copies of each of these genes. Those with SVAS have genetic mutations affecting only elastin. With only one good copy of the elastin gene, persons with WS and SVAS make inadequate quantities of elastin, which predisposes them to stiff blood vessels that are prone to stenosis (or vessel narrowing), restricting blood flow. However, some patients with WS (up to 20 percent) have no appreciable vascular abnormalities. Approximately 30 percent of affected patients have severe WS disease requiring surgical intervention to correct areas of stenosis and other abnormalities. Patients in the middle of these two extremes of WS have moderate vascular problems.
The variability of the clinical signs of WS suggests that other genes work with the elastin gene in determining disease severity. To investigate this further, Dr. Kozel used a genetic screening technology known as quantitative trait locus (QTL) mapping to identify regions of the mouse genome where genetic variation correlates to stenosis and hypertension severity. By looking under the “QTL peaks” in the data, she is identifying genes and pathways that, when combined with elastin insufficiency, change the severity of vascular disease outcome. Work to date has identified a role for a certain class of enzymes called oxidases as well as inflammatory cells in magnifying the elastin insufficiency clinical signs. Understanding these modifiers will allow the identification and study of new non-surgical treatments for diseases of elastin insufficiency. Several candidate drugs impacting ion channel function are currently under investigation in mouse models.
In addition to genetic traits, Dr. Kozel’s laboratory investigates the role of epidemiological factors and environmental influences on WS and SVAS disease severity. Her research group maintains a secure database that contains medical and genetic information from patients who have agreed to participate in her research, allowing investigation of how different aspects of these diseases interact. (For example, in addition to vascular concerns, individuals with WS might also have endocrine abnormalities, slower growth and development, and specific neurodevelopmental differences.) Dr. Kozel’s group collaborates with other groups whose work focuses on other aspects of WS and SVAS.
In her NHLBI/Clinical Center research, Dr. Kozel will continue to extend her basic laboratory research to human studies of WS, using noninvasive techniques to shed light on the clinical effects of the disease, including its progression over time. She will examine whether the genotype and disease traits she has identified in her mouse models correspond with the human version of the disease, which she has already found is the case with at least one gene associated with WS. She then aspires to translate the drug therapies she developed for the mouse models into medications for patients. As some drugs may have a different impact for different aspects of the disease, she will seek to target the right drug to the right patient, monitoring for any side effects.
Dr. Kozel is also interested in the effect that blood vessel changes in WS and SVAS have on organ function due to abnormal blood flow — particularly brain function, as WS is associated with neurocognitive disabilities. Increased knowledge in this area could potentially have an impact on other mental health matters as well. Additionally, WS and SVAS research might help shed light on hypertension and any other conditions associated with impaired blood flow as well as the aging process, in which elastin breaks down very slowly over time. Although she is studying rare diseases, Dr. Kozel’s work has the long-term potential of leading to improved clinical outcomes for many others.