This article has multiple issues. Please help improve it or discuss these issues on the talk page . (Learn how and when to remove these template messages)
|
Jacob M. Hooker is an American chemist and expert in molecular imaging, particularly in the development and application of simultaneous MRI and PET. He has contributed major advances on the entire spectrum of research from fundamental chemistry methodology with radioisotopes to human neuroimaging.[ citation needed ]
Hooker grew up just outside of Asheville, North Carolina and attended Enka High School. He graduated from North Carolina State University in 2002 with bachelor of science degrees in Textile Chemistry and Chemistry. He then earned his doctorate of philosophy in Chemistry at the University of California, Berkeley, mentored by Professor Matt Francis. After hearing a neuroimaging presentation in 2006 by National Medal of Science recipient Joanna Fowler, Hooker immersed himself in postdoctoral training under her mentorship at the Brookhaven National Laboratory. Fowler recalls having Jacob as a postdoc "getting him was like winning the lottery" "He's going to ask questions we haven't thought of before." [1] Hooker conducted his postdoctoral training with Fowler as a Goldhaber Distinguished Fellow, developing new neuroscience-oriented imaging methods and protocols.
Hooker relocated to Charlestown, MA in 2009 at the initiation of his independent research career at the Martinos Center. He co-designed and scratch-built a cyclotron and radiopharmacy facility housing a Siemens Eclipse HP Cyclotron, completed early 2011. The production and imaging facility – part of the Martinos Center Research Core – provides imaging tools for all stages of translational research.
The mission of his academic research lab is "to accelerate the study of the living, human brain and nervous system through development and application of molecular imaging agents." An organic chemist by training, Hooker and his research group are devoted to enhance understanding of the healthy brain and dysfunction in diseases including Alzheimer's, Autism and Schizophrenia.[ citation needed ]
His research focus centers on the themes of neuroepigenetics, radiochemistry methods development and neuroimaging methods development; highlights are provided in the following section.
Hooker has published over 100 papers [2] most notably in the domains of:
Work from Hooker's group published in August 2016 – Wey & Gilbert et al 2016 Science Translational Medicine revealed the first visual maps of neuroepigenetic function in the living human brain using the Class-I histone deacetylase (HDAC) PET imaging probe [11C]Martinostat. [3] This work demonstrated a link between quantitative HDAC maps of the brain and the expression of plasticity and disease-related genes under HDAC control. The human imaging report was built on a background of tool development in the Hooker lab spanning seven years, wherein small molecule histone deacetylase (HDAC) inhibitors were systematically screened and refined to resolve chemical leads with Class-I HDAC isoform selectivity, outstanding brain penetrance and appropriate binding kinetics.[ improper synthesis? ] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] The first-in-human imaging paper set the stage for Hooker's ongoing work to measure and map HDAC density, distribution and connectivity in diverse diseases, in vivo.
Hooker and his colleagues have made remarkable advances innovating in chemical and radiochemical synthetic methods to increase efficiency and expand capabilities of PET imaging. The most common radioisotopes for medical imaging agents, carbon-11 and fluorine-18, have a half-lives of 20.4 and 109.8 minutes, respectively. This presents significant demands in streamlining chemical synthesis steps and maximizing reaction yields in order to resolve sufficient quantities of radiotracer to complete required quality control steps before a dose can be 'released' for injection into a human subject. A critical element to this innovation has been the collaborative research environment cultivated within Hooker's lab to rethink dogmatic approaches to chemical endpoints or adapt cutting-edge organometallic chemistry to meet the needs of radiotracer synthesis.
Research Highlights in Radiochemistry
A new application for radiolabeled glucose: The main energy source of the brain, glucose, provides a significant biological foothold to image brain activity via energy use through cellular uptake and trapping of the glucose analog, [18F]fludexyglucose (FDG). Since the mid-1970s, FDG has been applied as a 'bolus' at the beginning of an imaging experiment with regional uptake measured and mapped after a waiting period during which brain cells unknowingly substitute radiolabeled FDG for normal glucose. Like long-exposure photographs, bolus FDG PET imaging paradigms are robust and valuable in identifying otherwise-inaccessible tissue types with differential metabolism (e.g. cancerous tumors, post-ischemic myocardial lesions, hypometabolic brain regions following aneurysm), but lack kinetic detail.
Despite some 40 years of [18F]FDG access and research, the dynamics of glucose utilization in response to brain activation remain poorly understood. Through innovations in radiotracer delivery and PET image processing, Prof. Hooker and his team were able to develop a method for brain glucose monitoring that produced something more like a movie, reporting changes in glucose use in response to multiple stimuli during a single PET scan. [21] The lab is now expanding the concept of dynamic, functional PET imaging to measure real-time neurotransmitter release in the living human brain.
Evidence of glial activation in the brain with chronic low back pain: In a similar reconfiguration of existing tools, Hooker and his faculty colleague and fMRI expert, Marco Loggia were the first to use the novel technology of integrated positron emission tomography-magnetic resonance imaging with the radioligand [11C]-PBR28 to demonstrate increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. [22] The work not only provided a new biological mechanism to explore in chronic pain treatment, it also helped to spark a major programmatic theme at MGH in neuroinflammation; borne from this was the Boston-wide Neuroinflammation Think Tank which bridges together major stakeholders from academia, medicine, and the pharmaceutical industry.
In 2016, Hooker was named as a Phyllis and Jerome Lyle Rappaport MGH Research Scholar which acknowledges 'forward thinking researchers with the funding they need to take their work into uncharted territories'. His research proposal, entitled Visualizing Chemical Dysfunction in the Human Brain was awarded $500,000 over five years for its tangible vision to develop novel imaging tools and accelerate their application in in vivo imaging to understand normal brain growth, aging and function and draw comparisons to brain diseases such as schizophrenia, Alzheimer's disease, dementia and Autism.
In 2015, the Brain & Behavior Research Foundation acknowledged Jacob with an Independent Investigator Award for research piloting neuroimaging in patients with Schizophrenia. He was named by The Scientist magazine as a Scientist to Watch, and in an article dubbing him 'The Mind Mapper' was among inaugural winners of the Talented 12 Award from the American Chemical Society's C & E News. [23]
Hooker was named by the National Academy of Sciences as a prestigious Kavli Fellow for a five-year tenure (2012-2017) and as a Keck Futures Initiative Fellow (2013-2015).[ citation needed ]
In 2009 he became a Department of Energy recipient of the Presidential Early Career Award for Scientists and Engineers (PECASE) for pioneering research on adapting modern synthetic chemistry to the development of new tools for tracking and quantifying biochemical transformations and the movement of complex molecules in living systems, as well as outreach and mentorship to visiting students and scholars. [24]
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.
Butyric acid, also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula CH3CH2CH2CO2H. It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid is an isomer. Salts and esters of butyric acid are known as butyrates or butanoates. The acid does not occur widely in nature, but its esters are widespread. It is a common industrial chemical and an important component in the mammalian gut.
In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed acetate esters or simply acetates. Deacetylation is the opposite reaction, the removal of an acetyl group from a chemical compound.
Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.
[18F]Fluorodeoxyglucose (INN), or fluorodeoxyglucose F 18, also commonly called fluorodeoxyglucose and abbreviated [18F]FDG, 2-[18F]FDG or FDG, is a radiopharmaceutical, specifically a radiotracer, used in the medical imaging modality positron emission tomography (PET). Chemically, it is 2-deoxy-2-[18F]fluoro-D-glucose, a glucose analog, with the positron-emitting radionuclide fluorine-18 substituted for the normal hydroxyl group at the C-2 position in the glucose molecule.
Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs. However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.
Vorinostat (rINN), also known as suberoylanilide hydroxamic acid, is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.
Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.
Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced euchromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.
Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.
Histone deacetylase 7 is an enzyme that in humans is encoded by the HDAC7 gene.
Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene.
Brain positron emission tomography is a form of positron emission tomography (PET) that is used to measure brain metabolism and the distribution of exogenous radiolabeled chemical agents throughout the brain. PET measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data from brain PET are computer-processed to produce multi-dimensional images of the distribution of the chemicals throughout the brain.
Cocaine addiction is the compulsive use of cocaine despite adverse consequences. It arises through epigenetic modification and transcriptional regulation of genes in the nucleus accumbens.
Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications.
Epigenetics of depression is the study of how epigenetics contribute to depression.
Martinostat is a histone deacetylase inhibitor (HDACi) that is potent against recombinant class I HDACs and class IIb HDAC with low nanomolar affinities. In tissue CETSA assays, martinostat exhibits selectivity for class I HDACs. When tagged with the radioisotope carbon-11, martinostat can be used to quantify HDAC in the brain and peripheral organs using positron emission tomography. Martinostat was given a name that adopted the style of other HDAC inhibitors, such as vorinostat, entinostat, and crebinostat, that recognized the academic center in which it was developed, the Martinos Center for Biomedical Imaging.
David E. Olson is an American chemist and neuroscientist. He is an associate professor of chemistry, biochemistry and molecular medicine at the University of California, Davis, and is the founding director of the UC Davis Institute for Psychedelics and Neurotherapeutics.
Neil Vasdev is a Canadian and American radiochemist and expert in nuclear medicine and molecular imaging, particularly in the application of PET. Radiotracers developed by the Vasdev Lab are in preclinical use worldwide, and many have been translated for first-in-human neuroimaging studies. He is the director and chief radiochemist of the Brain Health Imaging Centre and director of the Azrieli Centre for Neuro-Radiochemistry at the Centre for Addiction and Mental Health (CAMH). He is the Tier 1 Canada Research Chair in Radiochemistry and Nuclear Medicine, the endowed Azrieli Chair in Brain and Behaviour and Professor of Psychiatry at the University of Toronto. Vasdev has been featured on Global News, CTV, CNN, New York Times, Toronto Star and the Globe and Mail for his innovative research program.