For my doctoral thesis:
I work in the Hamza lab at the University of Maryland, College Park.
Our lab is interested in uncovering specific molecules and pathways involved in heme homeostasis.
Why heme?
* Heme is a
prosthetic group of proteins that perform a variety of biological
processes such as xenobiotic detoxification (cytP450),
oxygen transport (hemoglobin), respiration (COX), circadian
rhythm (Rev-erb) and more recently microRNA processing (DGRC8).
* Heme is the most bioavailable form of iron. Iron deficiency anemias
are a major nutritional disorder- iron is not very soluble at the pH of
the duodenum and it is usually found complexed with compounds such as
phytates.
So, we hypothesize that specific molecules and pathways exist of heme uptake and trafficking.
Rationale
Heme is a tetrapyrole with iron in the middle. It is synthesized in
most eukaryotes via a highly conserved multistep pathway that is
shared between the mitochondria and cytoplasm. The last step of
addition of iron in the empty prophyrin ring catalyzed by the enzyme
ferrochelatase occurs in the mitochondria. Its synthesis is tightly
regulated by heme itself, oxygen, availability of iron and is
coordinated with the presence of apo-hemoproteins. Heme is a hydrophobic molecule and is cytotoxic
due to its peroxidase activity. Once it is synthesized, it has to be
transported out of the mitochondria to be incorporated into a
hemoproteins found in different cellular compartments.
So how does a hydrophobic and cytotoxic molecule get out of the mitochondria and be incorporated into hemoproteins?
It was important to find a way to uncouple heme biosynthetic pathway
from trafficking becuase synthesis is tightly controlled and anything
to manipulate it leads to pleiotropic effects (naturally occuring
disorders in heme biosynthesis are called "porphyrias"). Our lab has
identied C. elegans, a free living nematode as a very good model system becuase it lacks the heme biosynthetic pathway (Rao et al, PNAS).
I took a genomics approach and performed a microarray analysis using
RNA from worms grown at different heme concentrations. From the microarrays, I have identified hrg-1 and hrg-4, as putative heme transporters in worms.
So, that was it in brief, you can read more about it at Dr.Hamza's website.
Undergraduate work: