Research areas
The major areas of research interest are detailed below:
Iron and anemia
A major focus of current research work is in studying iron homeostasis in women, non-pregnant and pregnant. In non-pregnant women, we are evaluating optimal ways for oral iron supplementation to treat iron-deficiency. In pregnancy, ongoing work investigates handling of iron in the placenta, how the iron status of the mother influences the fetus and the role of the placenta in the processes involved. In this context, we currently study those with uncomplicated pregnancies and those with gestational diabetes mellitus.
We have also been involved in studies on anemia of inflammation. In this context, we study derangements in iron homeostasis in those with inflammatory bowel diseases and how the presence of Helicobacter pylori infection affects iron homeostasis. Our past work has shown that several events involved in iron homeostasis are deranged in chronic inflammatory states, often resulting in anemia of inflammation, which is challenging to treat in clinical practice. Our work on inflamed mice has documented alterations in duodenal proteins involved in absorption of dietary iron. This provides an explanation for the observation that absorption of dietary iron is often decreased in inflammatory states. Broadly similar changes were seen in patients with chronic inflammatory diseases where, in addition, our work has shown that when anemia and inflammation (opposing stimuli that regulate hepcidin) coexist, the effect of anemia predominates over that of the latter.
We have also been involved in work on factors (such as ATOH8 [a transcription factor] and BMPER [bone morphogenetic protein-binding endothelial cell precursor-derived regulator]) that influence hepcidin (central regulator of systemic iron homeostasis) expression and hence, iron homeostasis. In addition, we are also involved in studies to evaluate the effect of micronutrient supplementation on anemia, in children under 5.
Given below are on-going and completed intra- and extramurally funded research projects in the above areas.
Iron metabolism in pregnancy
In pregnancy, our ongoing work investigates handling of iron in the placenta, how the iron status of the mother influences the fetus, and the role of the placenta in the processes involved. We currently study those with uncomplicated pregnancies and those with gestational diabetes mellitus (GDM). Other areas that have been and continue to be studied in pregnancy include investigating links between iron and development of gestational diabetes mellitus, and between vitamin D and anemia in pregnancy. Another recent avenue of exploration is in attempting to study associations between iron deficiency in pregnancy and pre-term labour.
Given below are on-going and completed intra- and extramurally funded research projects in this area.
Iron and diabetes mellitus
Dysregulation of iron metabolism has been postulated to play a role in the pathogenesis of diabetes mellitus. Such dysregulation is associated with both insulin resistance and impaired insulin secretion by the pancreatic beta cells. However, the underlying mechanisms involved are not clear. Planned and on-going work in the lab is aimed at investigating these aspects, at the molecular and functional level using in vitro, ex vivo and in vivo approaches.
Using animal models of dietary and genetic iron overload, we are investigating the effect of iron on insulin resistance and beta-cell function. In our studies involving humans, the effects of oral iron on insulin secretion kinetics and glucose tolerance are being evaluated. We are currently engaged in studying the possible involvement of adipose tissue macrophages (ATM) in the development of insulin resistance. It is envisaged that these studies will help elucidate the role of iron as a risk factor for diabetes mellitus,
Our past work in this area has involved elucidating links that underlie the oft-reported association between diabetes mellitus and high body iron stores. We have shown that increased intracellular iron in hepatocytes affected insulin signaling in these cells. Iron increased basal activation of the Akt pathway (involved in intracellular insulin signaling), in the absence of insulin. Responses to insulin in such hepatocytes were found to vary, depending on whether the accumulation of iron within the cells occurred in vitro or in vivo. We have also shown that hepcidin appears to influence the development of diet-induced inflammation in adipose tissue and insulin resistance. In keeping with this, we have recently reported that serum ferritin and hepcidin were elevated in newly diagnosed diabetics, indicating dysregulated iron homeostasis. Serum ferritin correlated positively with insulin resistance in these patients. These observations provide important insights into how iron and diabetes mellitus are linked.
Given below are on-going and completed intra- and extramurally funded research projects in this area.
Iron and wound healing
There is an urgent need to develop new and effective therapeutic strategies to promote wound healing in patients with chronic non-healing ulcers. Iron is essential for normal wound healing. However, iron tends to accumulate in chronic wounds, and it is thought to impair the healing process in this setting. The underlying mechanisms involved are, however, not clear.
Using animal models of cutaneous wounds, we aim to investigate the role of iron as a factor that inhibits the process of wound healing. In collaboration with the Department of Physical Medicine and Rehabilitation at CMC, Vellore, we have initiated translational research work, which will look at the pathophysiological role of iron overload that is often seen in pressure ulcers, a common cause of chronic non-healing ulcers. In addition, our work in this area is also focused on evaluating iron chelation as a novel therapeutic modality to accelerate healing in such wounds.
Given below are on-going funded research projects in this area.
Iron and liver disease
Our work in this area is currently focused on the role of iron in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). On going work on primary hepatocytes is looking at the cross-talk between ferritinophagy, ferroptosis, oxidative stress and steatosis.
In the past, our work on alcoholic liver disease has shown that several iron-related parameters in the liver were altered, but that this did not result in hepatic iron overload. This latter finding is significant in that it shows that iron accumulation is not an invariable finding in alcoholic liver disease, as tends to be reported in many publications from the western world, which have based their statements merely on high serum ferritin levels, often used as a marker of increased iron stores, but unreliable in the presence of inflammation, as it is an acute phase reactant. In addition, liver damage is also known to result in increased levels of ferritin in blood. Our work in this area has shown that hepatic iron accumulation not an invariable finding in alcoholic liver disease. On the contrary, we have shown that alcohol-induced decreases in hepatic iron levels in a mouse model. Based on this, we have suggested that this may contribute to suppression of hepcidin that has often been reported in those with alcoholic liver disease. We have also shown that such hepcidin suppression is not due to liver dysfunction per se (as hepcidin is synthesized mainly in the liver). Our studies on patients with chronic liver disease support this contention, as little correlation was found between serum hepcidin levels in these patients and markers of biosynthetic function of the liver. Our work has also shown that the hepcidin response to higher body iron levels and/or inflammation appeared to be functional in these patients, despite the presence of liver disease, thereby showing that liver dysfunction per se does not seem to be responsible for the derangements seen in iron homeostasis in chronic liver disease. These observations have contributed to an improved understanding of dysregulated iron homeostasis in such patients.
Iron and endometriosis
In collaboration with the Department of Reproductive Medicine and Surgery, we are interested in exploring the role of iron overload as a possible cause for infertility in women withe endometriosis. This work is omgoing work and is funded by intramural grants.
Other areas of research interest
In addition to our current primary focus on iron metabolism, we have also been working on NSAID-induced enteropathy and nephropathy, and have a special interest in medical education. In addition, Molly Jacob has been involved in work on the pharmacogenomics of treatment-resistant schizophrenia.