Research

Madiraju, Murty V.V.S., Ph.D.

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Contact: murty.madiraju@uthct.edu

Research Interest:

Mycobacterium tuberculosis proliferation mechanisms, Replication Initiation and Cell Cycle.

Research Overview:

We are interested in understanding the proliferation mechanisms of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Mtb is also the leading cause of morbidity and mortality in AIDS patients. It is known that following infection, Mtb frequently enters a latent state for extended periods and subsequently, under appropriate conditions or following immune suppression, revives, multiplies and causes diesase. Regulation of DNA replication is one of the important factors affecting Mtb ability to enter into and exit from latency. The development of novel therapeutic agents to control Mtb infections in HIV infected patients as well as other individuals is severely hindered by our limited understanding of the initiation and regulation of Mtb DNA replication and its coordination with other events in cell cycle. DNA replication is initiated at a unique site on the chromosome called oriC and is believed to occur when the initiator protein DnaA interacts with oriC and recognizes the DnaA protein reconginition sequences called DnaA-boxes to catalyze the formation of initiation complex. It is largely unknown how this process is regulated at different stages of growth and infection.

Mtb operates serveral regulatory networks for its optimal survival upon infection, and one such regulatory network is histidine-aspartate two component regulatory signal transduction system (2CRS). MtrAB is one of the essential 2CRS that includes a membrane bound sensor kinase MtrB and cytosolic response regulator MtrA. In response to changes in environmental stimuli, MtrB undergoes autophosphorylation and then transfers its phosphate to MtrA for modualting gene expression. Recent work in our laboratory revealed that dnaA promoter and oriC are MtrA targets. While these studies signal an intimate connection between the two essential pathways: DnaA mediated oriC replication and MtrAB 2CRS, it is largely unknown how oriC replication is regulated by MtrA response regulator and its phosphorylation status, specifically during active and persistent growth states. Our current research explores this exciting area of research using a combination of genetic, molecular biological and biochemical approaches. Detailed knowledge on Mtb oriC activation mechanisms both during active growth and exit from latent state is an essential prerequisite for the development of drugs to inhibit the initiation of replication and thereby prevent the development of potentially lethal infections of Mtb.

We recently defined the MtrA regulon by ChIP-Seq, and are now focussing on dissecting the roles of MtrAB signal transduction pathway on Mtb proliferation upon infection.

Selected Papers and Abstracts:

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