Professional Experience
Current Experience
Specifically, as a senior pharmacovigilance/regulatory affairs consultant at Chattem my main role was to provide technical/scientific support as well as statistical/data analysis for the Department of Product Safety & Regulatory Affairs, Marketing and Product Development to reduce outside consulting costs. Additionally, I was responsible for all pharmacovigilance (PV) activities relating to adverse events (AE), drug safety, and post-marketing surveillance to ensure regulatory compliance as well as serving as the primary liaison for Chattem’s international PV contract. I reviewed incident data to develop medical terminology, causality and chronologies for AEs to determine if investigations are warranted and initiated in compliance with FDA and Code of Federal Regulations (CFR). Moreover, I chaired the AE Committee Review meetings and prepared Food & Drug Administration (FDA) Medwatch 3500A forms for over-the-counter (OTC) drugs, devices and dietary supplements. I also conducted InfoMed tracking system database queries, data mining and literature searches to generate trending analyses, establish product histories and detect safety signals. Additionally, I wrote and edited standard operating procedures (SOPs), promotional material for health professionals, white papers, technical documents and New Drug Application (NDA) Periodic Safety Update Reports (PSURs). Another project I led was the implementation of the customized versioning and coding of the InfoMed database program to improve efficiency for Consumer Affairs, Quality Control and the Department of Product Safety & Regulatory Affairs. I regularly conducted drug regulation reviews, CFR and OTC drug monograph interpretation and risk analyses. I gave guidance to six consumer affairs representatives on technical inquiries and disposition of complaints. In a supporting role, I was a team member for non-clinical/clinical studies including protocol design, monitoring and management. I conducted reviews of labeling, artwork and advertising materials for claim support justification, appropriate language and compliance with federal and state regulatory agencies. Furthermore, I reviewed ingredient listings and formulations for safety issues as well as active and inactive ingredient regulatory permissions. All the while, I utilized effective communication and proficient computer skills such as Excel, Word, and PowerPoint daily.
Postdoctoral Research
The roles of Egr 2/3, mTOR and Cbl-b during anergy induction
The overall goal of the Powell Lab is to try to understand the biochemical and molecular pathways involved in T cell tolerance and activation. T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. In order to identify molecules/pathways involved in the negative regulation of lymphocytes we utilized high-dimensional microarray analysis of T cells under conditions which promote or inhibit the induction of anergy. From the set of multiple genes identified, we targeted the zinc-finger transcription factors, early growth response gene-2 (Egr-2), and subsequently Egr-3 as key negative regulators of T cell activation. Overexpression of Egr-2 and Egr-3 was associated with an increase in the E3 ubiquitin ligase Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr-3 knockout mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance. These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program.
Indeed Cbl-b has been shown to be upregulated during anergy induction and mediate its effects in part through inhibition of PLC-gamma phosphorylation. Consequently, Cbl-b deficient T cells and mice are resistant to the induction of tolerance in vitro and in vivo. However, while Cbl-b upregulation can account for the immediate defects seen in anergy, Cbl-b cannot readily explain the long-term hyporesponsiveness. Alternatively, rapamycin, a pharmacological inhibitor of mTOR, has been shown to promote stable T cell anergy under full activation. Therefore, we hypothesize that the effects of Cbl-b are ultimately related to mTOR activity of the cell. We demonstrate that rapamycin inhibits T-cell activation in vitro in both wild-type or Cbl-b -/- clonotypic T cells and that activated Cbl-b -/- T cells exhibit higher levels of rapamycin-sensitive phospho-p70 than wild-type cells. To further test this hypothesis in vivo, we adoptively transferred wild-type or Cbl-b -/- clonotypic T cells a model of peptide-induced anergy in the presence or absence of rapamycin. Recipients of Cbl-b -/- T cells were resistant to peptide-induced anergy compared to wild-type controls. However, this resistance to tolerance in the Cbl-b null mice was reversed by the presence of rapamycin. That is mTOR inhibition promoted anergy even in the Cbl-b T cells and this inhibition by rapamycin appears to be dependent on the generation of CD4+CD25+FoxP3 T reulatory cells. These data support the view that mTOR acts downstream of Cbl-b mediated inhibition and is critical in determining T cell activation versus tolerance. We sought to understand the biochemical mechanisms by which rapamycin promotes T regulatory cell generation as well as determine the regulation and targets of Egr-2/3 in T cells during tolerance and activation. Additionally, we determined the role of Egr-2/3 in established in vivo models of tumor tolerance or autoimmunity by utilizing TCR transgenic T cells specific for self-antigen from wild-type, Egr-2 -/-, Egr-3 -/- or Egr-3 overexpressing mice.
Furthermore, I was involved in other projects looking at the in vivo roles of additional genes and pathways involved in T cell tolerance and activation. In one such project, we examined how the proliferation associated SNF-2-like gene (PASG) controls epigenetic changes via DNA methylation in T cells, while another project focused on the ability of Homer 2/3 to regulate NFAT in T cells. Additionally, through collaboration we have been able to show that low molecular weight hyaluronan fragments can acts as an adjuvant in vivo via Toll-like receptor 2 (TLR2)
Graduate Research
The role of the MSP/RON signaling pathway in CR3 activation and the regulation of inflammation in vitro and in vivo
The Correll Lab studies the physiological roles of the RON receptor tyrosine kinase and its ligand, MSP, in hematopoiesis and oncogenesis as well as the role of MSP/RON in the regulation of macrophage biology, inflammation and innate immunity. MSP exerts multiple effects on resident populations of macrophages through the RON receptor. For example, MSP/RON activation leads to the induction of shape change, suppression of LPS/cytokine-induced nitric oxide production, as well as the promotion of complement-mediated phagocytosis.
My thesis project investigated the ability of MSP/RON to induce CR3-mediated phagocytosis and CR3-mediated ICAM-1 binding. We have shown that these processes are dependent the RON receptor, the alphaMbeta2 integrin, tyrosine kinase activity, phosphatidylinositol 3-kinase as well as the atypical protein kinase C zeta. This research helps delinate signaling pathways by which receptor tyrosine kinases are able to activate integrins. My thesis project also focused on the in vitro and in vivo roles of MSP/RON in the regulation of inflammation, macrophage activation and cell-mediated immune responses. Additionally, we utilized RON-deficient mice to study the in vivo role of RON in regulating hepatic inflammation as well as susceptibility to infection with Listeria monocytogenes.
Centocor
At Centocor, I supported studies in both the Immunology Department as well as the Pharmacology & Toxicology Department. Primarily, I assisted in experiments validating the toxicology and efficacy of Infliximab/Remicade (chimeric TNF-alpha blocking antibody) in in vivo models of arthritis. Other responsibilities included: analyzing clinical chemistries of serum samples, ELISA assays, ascites production, laboratory animal dosing and sample collecting, animal care and husbandry, information searches and animal cell culture.