Research Synopsis

Developing assays for small RNAs in human cell lines and tissue samples and developing software to interpret small RNA signatures as diagnostics or theranostics.

Profile

Clark Jeffries’s research focuses on design and interpretation of assays of small RNAs as agents of signaling that may be causally upstream of many other types of biomarkers. Surveys of microRNAs in nuclear and cytoplasmic compartments of human neural progenitors have surprisingly revealed rich nuclear inventories as well as sequence patterns that seem characteristic of nuclear import.  This implies that microRNAs might well be as important in regulation of nascent transcription as they are known to be in regulation of translation.  Nuclear import and the small size of microRNAs (precluding some types of immune response), suggest their use at the very heart of gene regulation.

The active projects in the lab include

1. Computer analysis of small RNA sequencing data.  Current technologies generate millions of "reads" of ~35  bases within which subsequences in random windows reflect RNA species.  A pipeline specifically dedicated to understanding small RNAs has been created and in particular the problem of normalization between "lanes" has been solved (the same sample duplicated in two lanes can generate many times more reads in one than the other, so the goal is to find consistency within wildly different data).  This program leads to selection of small RNAs that distinguish control from case.  Then the same small RNAs can be probed by custom biochemical technologies that are far more reproducible and precise than gross sequencing data.  The outcome can be new diagnostics of great value to patients and clinicians.
2. A program with Prof. D. O. Perkins, MD, has centered on isolation of small stem cells from human blood.  While difficult to control, the cells have been cultured in some cases for more than one year. Some have been treated with published protocols to differentiate them into much larger cells that are positive for neuronal markers.  It seems possible that this technology might eventually allow generation of neuronal cells from living patients with mental illnesses, thus suggesting a variety of investigations of effects of medicines on a patient-specific basis.  Presently selection of treatment for persons with prodromal psychosis is an important unsolved problem in psychiatry.
3. In conjunction with Prof. W. K. Kaufmann, PhD, we have devised methods for "system identification," traditionally an engineering exercise in which one goes from lab data to a model of a system that can be used to control a machine.  Cell cycle data from cells responding to irradiation stress has been used to connect data to checkpoints for DNA damage in cells.  This work pertains in the present instance to melanoma research but could be expanded to other types of assay data for stressed cells.  The complex dynamic signatures of markers may indeed prove more informative than static signatures; this should include small RNA signatures.

Appointments

• 1987-1992  Lecturer, Assistant Professor, Associate Professor, Professor of Mathematical Sciences, Clemson University, Clemson, SC
• 1998-2004 IBM Microelectronics Division, Senior Programmer, Research Triangle Park, NC:  IBM Master Inventor 2003-2004
• 2005-present   Research Scientist, Renaissance Computing Institute
• 2006-present   Research Professor, University of North Carolina Eshelman School of Pharmacy

Recent funded research

NIH/NIEHS       [W. Kaufmann (PI)] 2008-2013 Role:  Co-Investigator
P01  ESO14635-02          
"The System of Response to DNA Damage Suppresses Environmental Melanogenesis"
The goal of this research is characterization of melanoma through mRNA profiles and deduction of a mathematical model of fibroblast response to radiation that reflects and then predicts lab data.

Stanley Medical Research Foundation    [D. Perkins (PI)] 2008-2010 Role:  Co-Investigator
08R-1978             
"Viral miRNA Detection in Post-mortem Cortical Tissue"
The goal of this research is characterization of viral miRNA profiles and deduction putative bioinformatic patterns.

NIH/NIGMS     [A. Tropsha (PI)] 2008-2013 Role:  Co-Investigator
2R01GM066940-05A1
“Predictive QSAR Modeling”
The major goal of this project is to develop a universally applicable and robust predictive QSAR modeling framework that will afford highly significant, externally validated, and predictive QSAR models of important biological endpoints.
Role:  Co-Investigator

The Foundation of Hope  [D. Perkins (PI)] 2005-2011
"Genetic Control of Neurodevelopment in Schizophrenia: A model based on olfactory neurons from living humans"
To determine if neuronal cells from the olfactory epithelium may provide insights into altered neurodevelopment in individuals with schizophrenia.
Role:  Co-Investigator

Pardee Foundation  [A. Tropsha (PI)] 2006
“Systematic discovery of automatic gene regulation modules in cell cycle dynamics”
The major goal of this project is experimental investigation of biochemistry of noncoding RNA hairpin molecules as regulatory agents of apoptosis in breast cancer.
Role:  Co-Investigator