Dr. Cox obtained her Ph.D. from the Curriculum in Genetics and Molecular Biology at University of North Carolina – Chapel Hill in 1992.  She carried out her thesis work in the laboratory of Dr. Mark Peifer where she used the model organism Drosophila melanogaster to uncover how the highly conserved protein Armadillo/beta-catenin functions in cell-cell adhesion and cell signaling during development.  After a year as a postdoctoral fellow in the Peifer lab, she went on to do a postdoctoral fellowship in the laboratory of Dr. Alan Spradling in the Department of Embryology, Carnegie Institute for Science in Baltimore, MD.  There, she began studying the molecular mechanisms governing mitochondrial movement and function during Drosophila oogenesis.  In 2008, Dr. Cox obtained an independent tenure track position at Uniformed Services University in the Department of Biochemistry and Molecular Biology where she continues her research on mitochondrial function, homeostasis, and quality control during development and disease.

Rachel T. Cox, Ph.D.

Relevance

Decreased mitochondrial function is closely linked to aging and many age-related diseases, including those involving neurodegeneration.  These important organelles make ATP, intermediate metabolites, and regulate programmed cell death. To fulfill these roles, mitochondria require proteins and products supplied by the cytoplasm and nucleus, a process that relies on tightly regulated signaling and coordination between the compartments.  There are many aspects of the complex relationship between mitochondria and the cytoplasm that we do not fully understand.  To better assess the influence of mitochondrial decline on aging and age-related diseases, it is critical to identify and understand the genes and mechanisms controlling mitochondrial function in vivo in multicellular organisms.  We have developed Drosophila as a powerful model system to study mitochondria, combining imaging, genetics and biochemistry. Our long-term goal is to understand the cellular processes responsible for supporting and maintaining functional mitochondria during tissue homeostasis and development.  This is a pressing need due to the causative effect mitochondrial dysfunction has on aging and a variety of age-related diseases.

Background

            Mitochondria are cellular organelles that produce the majority of ATP in eukaryotic cells.  Mitochondria are unique in that they contain their own DNA, mtDNA.  While this DNA is small, approximately 16kb in metazoans, it is critical for normal mitochondrial function.  Because mitochondria cannot be made de novo, mitochondria and mtDNA are inherited through the mother’s oocyte cytoplasm.  In addition, mtDNA and mitochondria can undergo damage and become non-functional.

            In the last twenty years, an increasing number of diseases have been linked to mutations in either mtDNA or nuclear genes encoding mitochondrial proteins.  While the general observation that faulty mitochondria can lead to disease may not be surprising given the important role mitochondria play in cellular function, the specificity with which only certain cell types are affected by single mutations has been.  In addition, there is mounting evidence for a role of mitochondrial dysfunction in common diseases, such as neurodegenerative disease and diabetes.

Research interests of the Cox lab

The broad interests of the Cox lab are studying how mitochondria change shape, location, physiology and mtDNA content in response to developmental changes, and elucidating which genes and molecular pathways regulate these changes.  To address these general questions, we use the model system Drosophila melanogaster.  The advantages to using Drosophila are that their rich genetic history allows rapid and straightforward mutant acquisition, and researchers understand much about organ and tissue development.  Mitochondria can be imaged in fixed and live tissue at single organelle resolution.  It is important to note that an estimated 75% of human disease genes have a functional homolog in flies.  The overwhelming similarity of genes and molecular pathways between humans and flies allows researchers to apply knowledge gained from Drosophila to elucidate the causes of human disease.

The role of Clueless in mitochondrial maintenance

             Clueless (Clu) is involved in mitochondrial localization and function.  Clu is a highly conserved ribonucleic acid binding protein (RBP) that is required to support mitochondrial function.  Drosophila lacking Clu die quickly with damaged, non-functional mitochondria.  We have shown Clu binds mRNA and associates with the ribosome.  In addition, Clu physically and genetically interacts with components of the mitophagy machinery, PINK1 and Parkin. Clu forms dynamics stress-sensitive ribonucleoprotein particles. Our current model is that Clu particles act to regulate metabolic output during times of stress by regulating mitochondrial function.

Identifying dietary radioprophylatic agents to guard against acute irradiation damage

            Exposure to acute ionizing radiation (IR) from occupational, environmental, or therapeutic sources can cause severe injury to the gastrointestinal (GI) tract. Currently, very few pharmacological interventions are available to enhance radiation resilience, and there is a profound lack of established mechanisms for effective prophylactic protection. Our laboratory has developed a Drosophila as a model to characterize the conserved cellular and molecular responses to IR. We have identified two dietary agents—manganese chloride and the radioresistant fungus Aureobasidium pullulans (A.p.)—that significantly extend survival and improve gut cell nuclear morphology when administered prior to IR exposure. Our future goals are to identify specific molecular signatures and antioxidant pathways that confer prophylactic protection to the gut. Since cellular pathways and tissue functions are highly conserved between flies and vertebrates, these data will reveal novel biological targets for the future development of effective strategies to mitigate radiation-induced GI injury in higher model systems.

Mitochondrial RNase P and disease

            Mitochondrial tRNA (mt-tRNAs) are processed on their 5’-end by a three-protein complex called mitochondrial RNase P (mtRNase P).  This processing not only matures mt-tRNAs but is also critical for maturation of the other mtRNA species encoded in mtDNA.  Human mutations in either the protein complex or mtDNA can decrease processing, leading to mitochondrial dysfunction and disease.  We are characterizing the in vivo role of mtRNase P on tissue development and homeostasis to better understand the disease etiology in humans.

Current funding and support: NIH/ORIP

Previous funding and support: CNRM (Center for Neuroscience and Regenerative Medicine), USUHS Start Up funds, USUHS Exploratory grant, NIH/NIGMS, CDMRP, CHIRP (Collaborative Health Initiative Research Program, NHLBI/DoD)

 Publications

https://pubmed.ncbi.nlm.nih.gov/?term=cox+rt+drosophila&sort=date