Michael Johnson
Michael Johnson
E-mail: johnson.michael@husky.neu.edu
Department: Pharmaceutical Sciences
Advisor: Alex Makriyannis
Collaborators: Sri Sridhar, David Janero
Biography
My career began in the biopharmaceutical industry when I started working at Watson Pharmaceuticals (as an analytical chemist) in 2006 after graduating from the SUNY College of Environmental Science and Forestry with a B.S. in Biotechnology magna cum laude. After a year and a half, my local facility was closed and my position was outsourced ��” so I made a lateral move to Boehringer-Ingelheim Pharmaceuticals where I provided analytical support, research and development for the crystallization, chemical development, and strategic outsourcing departments. In 2009, I decided to further my career through the pursuit of a Ph.D. in Pharmaceutical Science at Northeastern University- where I was awarded an academic excellence fellowship, the Provost’s Certificate of Excellence in Research Award, an NSF/NCI (IGERT) Interdisciplinary Nanomedicine fellowship, an American Foundation for Pharmaceutical Education fellowship, and a Certificate of Advanced Study in Management (from the Northeastern University College of Business Administration.)
My research, the development of a highly selective, theranostic nanoplatform-based inhibitor of, and imaging modality for, human monoacylglycerol lipase (MGL) has driven me to research and develop new technologies and strategies for treating metastatic disease. Epidemiological data, from a 2010 meta-analysis, forecast that more than 12% of female newborns in the United States will be diagnosed with breast cancer within their lifetime. Those with aggressive forms of the disease will have less than a 25% chance of surviving 5 years after diagnosis. Without pharmacological intervention, breast cancer will remain a significant, global health problem for the foreseeable future. Currently, the limiting step in the breast cancer drug discovery initiative is the identification of highly selective imaging and therapeutic agents for the early diagnosis and treatment of the disease. The discovery, design, and characterization of a novel, multimodal, theranostic nanoplatform, which has the unique ability to diagnose disease states while showing real-time, traceable therapeutic efficacy, is the focus of my efforts. In addition to being a novel therapeutic tool, I argue that this platform will increase the efficiency of translation of new, medically relevant discoveries from the lab bench to the clinic.
MGL is a serine hydrolase that regulates endocannabinoid signaling. It has a typical serine-histidine-aspartate catalytic triad, belongs to the α/β hydrolase family, and is the major enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG); an endocannabinoid that is synthesized and localized in the membrane bilayer. Increased levels of 2-AG are considered antinociceptive, antiallodynic, anti-inflammatory and therapeutic for neurodegenerative disorders. Overexpression of MGL, and the resultant over-hydrolysis of 2-AG, elevates the level of protumorigenic signaling lipids in cancer cells. As such, MGL regulates a fatty acid network that promotes cancer pathogenesis. MGL inhibition has been shown to attenuate the growth, migration and invasion of aggressive/metastatic, prostate and breast cancer cells. The development of a highly selective imaging modality for examining functional MGL will be a key step in our understanding of the complete metabolic role this potential biomarker plays.
MGL transiently associates with cell membranes. To completely understand the mechanism of action of this enzyme, it is vital that we first unravel the structural dynamics of the MGL-membrane interaction and also MGL’s intracellular localization. MGL, like most lipases, exhibits interfacial activation and undergoes a transition from a “solution,” to a “membrane-associated” conformation; a process that involves attachment of part of its lid domain to the phospholipid bilayer. As a prerequisite for developing small molecule drugs that target MGL, it is essential to unravel how these conformational and spatial dynamics come about. I propose to achieve this by addressing three Specific Aims: (1) the development of a silica-coated, super-paramagnetic, iron oxide core/gold shell, theranostic nanoplatform (fLPA-SPIO@AuNS) — functionalized with a novel MGL inhibitor, (2) determination of the kinetics of MGL hydrolysis in a nanodisc biological membrane mimetic; with further characterization the nanodisc model using high resolution imaging techniques, and (3) the use a novel, “Michael probe” system to specifically label and image active human MGL.
Following graduation, I plan to return to work in the pharmaceutical industry and concurrently complete my Master of Business Administration degree. I wish to excel in the corporate world, to be an effective leader, innovator and entrepreneur and to have a deep understanding of the principles of management, marketing, investing and finance ��” while pioneering in the field of drug discovery and development.
Projects
Presentations
- Synthesis & Characterization of a Novel, Theranostic, Click-Enabled Nanoplatform , Michael J. Johnson, Codi Gharagouzloo, Dattatri Nagesha, Rajiv Kumar, Srinivas Sridhar, David R. Janero, Alexandros Makriyannis , Boston, MA, May 2012
- Conformational Analysis of a Native Membrane Associated Protein Incorporated Into Phospholipid Bilayer Nanodiscs: Implications for Drug Discovery, Mahmoud L. Nasr, Xiaomeng Shi, Michael J. Johnson, Hideyo Inouye, Nikolai Zvonok, John R. Engen, Lee Makowski, Alexandros Makriyannis , 14th Annual Symposium on Advances in Separation Science and Mass Spectrometry, Boston, MA, May 2012
- A Novel Approach for Detecting a Cancer Cell Biomarker in a Complex Proteome , Michael J. Johnson, Mahmoud L. Nasr, Xiaomeng Shi, Nikolai Zvonok, John R. Engen, Zhaohui Sunny Zhou, David R. Janero, Alexandros Makriyannis, Boston, MA, Mar 2012
- Studies on the Dynamic Properties of Human Monoacylglycerol Lipase in Nanodisc Model Membrane., Nasr M., Shi X., Karageorgos I., Johnson M., Halikhedkar A., Morgan C.R., Tian X., Zvonok N., Engen J.R., Makriyannis A., International Cannabinoid Research Society (ICRS), Chicago., Jul 2011