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Neurochemistry is the study of fundamental genetic mechanisms in the human body that regulate how chemicals govern the activity of nerve cells. The failure of these mechanisms can lead to the onset of devastating life-threatening and chronic diseases, foremost among them: Alzheimer’s, Parkinson’s disease, amyotrophic laterals sclerosis (ALS), autism, schizophrenia and major depression.
A second critical area of neurochemistry research is how cell signaling through molecules called cytokines regulate processes in the brain and in other organs. Cytokine dysregulation has been implicated in many diseases of the developing intestine and brain during gestation.
Over the past decade and more, Dr. Jack Rogers has been a leader in conducting research that has transformed the way seemingly separate neurodegenerative diseases are now viewed, revealing underlying common mechanisms at the genetic level. In doing so, Dr. Rogers and colleagues were the first scientists to identify a common therapeutic target—the Iron Response Element—on several of the genes that code for proteins implicated in neurodegeneration, findings which may successfully target the gene that encodes the amyloid precursor protein (APP) implicated in Alzheimer’s disease, and the gene that encodes the protein alpha synuclein in Parkinson’s disease.
To advance these findings, Dr. Rogers is moving forward from these basic mechanisms to the study of molecules that can reach the Iron Response Element—the common therapeutic target—and act to inhibit the production of the disease-causing proteins. This research is now in the in vivo testing stage using mouse models of the diseases.
Positive results in these tests will enable progression to clinical trials and, hopefully, to the development of drugs with impact across the neurodegenerative disease spectrum. The idea is to develop blockers of the genes that produce the “culprit” proteins at the pass before they can cause nerve damage. Other possible clinical benefits of this research relate to the potential of dietary interventions to protect against this neuro-degeneration.
See Dr, Rogers’ publications on https://connects.catalyst.harvard.edu/Profiles/display/Person/47607.
The Iron Response Element, a common Neurodegenerative Disease Therapeutic Target.
The common iron-responsive element motif in the 5’untranslated regions of the Alzheimer’s associated, amyloid precursor protein (APP), Parkinson’s associated, alpha Synuclein, transmissible spongiform encephalopathies (TSEs) associated Prion protein and now reporting on the amyotrophic lateral sclerosis ALS associated transcript, C9orf72, offers a novel approach to targeting multiple neurodegenerative diseases.
On The Cover: The image shows a predictive consensus tertiary RNA structure for the human APP IRE based on the two secondary structures reported. The image was generated by Sohan Mikkilineni, MIT. For details see the article by Cho et al., J. Biological Chemistry pages http://www.jbc.org/content/285/41/31217
The laboratory has screened multiple drug libraries containing thousands of both FDA approved as well as other novel small molecule drugs and neutraceuticals. One of these, JTR-009 is a small molecule whose mechanism is to modulate the binding of the IRP-1 RNA binding protein to the Iron Response Element stem loop. JTR-009 clamps onto the IRE and blocks the translation of the Alzheimer’s associated Amyloid precursor protein (figure below). Other novel small molecules, including BL-1 have been screened to target IREs associated with Parkinson’s disease and Prion disease and are currently under investigation, requiring testing in animal models and ultimately final testing in human clinical trials.
See Jack’s publications, https://connects.catalyst.harvard.edu/Profiles/display/Person/47607
Check out Dr. Roger’s and colleagues recent review in Neuroscience and Medicine, in press!
The 5’-Untranslated Regions of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-aconitase Iron-responsive Element; Novel Therapies for Amytrophic Lateral Sclerosis.
Jack Rogers, PhD Program Director, Associate Professor of Psychiatry-Neuroscience, Harvard Medical School, Director, Laboratory of Neurochemistry. He received his PhD from St Mary’s Hospital, University College London and postdoctoral research at MIT.
See Dr. Rogers’ publications, https://connects.catalyst.harvard.edu/Profiles/display/Person/47607
Dr. Catherine Cahill, Assistant Professor of Psychiatry-Neuroscience, Harvard Medical School, Principal Investigator, Laboratory of Neurochemistry. Dr. Cahill received her PhD from University College Dublin, Ireland. and did her post doctoral research in the Dept. of Immunology at the Babraham Research Institute, Cambridge, UK and at the Dana Farber Cancer Institute, Boston USA.
Dr. Cahill is expanding the lab’s research program to include developmental neurobiology, relevant to many psychiatric disorders in childhood, including autism spectrum disorders. A common thread running through these conditions is neuro-inflammation, an underlying cause which is now an area of intense interest. Dr. Cahill specializes in investigations of developmental regulation of the inflammatory response in the intestine and the brain. Her research has demonstrated that a dysregulated inflammatory response can have profound effects on the developing fetus leading to diseases such as necrotizing enterocolitis, a leading cause of death of premature infants. Neuro-inflammation is also implicated in brain disorders in fetal development.
Dr. Cahill has teamed up with Dr. Rogers on research aimed at understanding the impact of environmental exposures, including lead and manganese on the developing brain where neurodegenerative mechanisms may be at work earlier in life. Moving forward, Dr. Cahill hypothesizes that inflammation prior to birth, triggered by maternal infection, toxins, or bad nutrition, including iron deficiency, may be the underlying mechanism in some types of autism. Through further investigation of developmental regulation, a principal goal of Dr. Cahill’s work is to discover specific months and weeks during human gestation that are particularly vulnerable. Moving from “bench to bedside”, she then seeks to identify periods when the administration of anti-inflammatory drugs would have a protective effect and to achieve the ultimate goal of decreasing the incidence of autism and other psychiatric disorders associated with neuro-inflammation.
Dr. Cahill’s research aims at understanding the signaling pathways induced by pathogenic bacteria and the pro-inflammatory cytokine, Interleukin 1 beta to the induction of Interleukin-6 (IL-6), a cytokine associated with intestinal barrier dysfunction, peripheral inflammation and brain injury. Her work has revealed a novel cross talk mechanism between the inflammation associated transcription factors, Nuclear Factor kappa B and Activator protein 1 (AP-1), involving a kinase of the IKK complex, IKK alpha . Her recent research reports on differential expression of AP-1 during intestinal development which has significant implications for the understanding and treatment of inflammatory diseases of the neonatal intestine and associated brain white matter injury. Her research in the Neurochemistry lab aims to study how IL-1 and IL-6 are important players in the brain, leading to injury, neuro-degeneration and developmentally associated psychiatric disorders.
See Dr. Cahill's publications on; https://connects.catalyst.harvard.edu/Profiles/display/Person/87371
Dr. Xudong Huang, Assistant Professor of Psychiatry Neuroscience, Harvard Medical School, Co-director of Neurochemistry received his PhD from MIT (Chemistry) and completed his postdoctoral training at the Neuroscience Center Massachusetts General Hospital. His major research activities and achievements are centered upon:
1. pursuing CNS drug discovery and its commercialization (together with Dr. Jack Rogers); 2. validating the association of environmental stressors such as exposure to metals and metal oxide nanoparticles with neurodegeneration using in vivo molecular imaging modalities; 3. exploring novel applications of big biomedical data analytics using clinical data, NoSQL- and Hadoop-based big data technologies, and R/Python programming languages.
Together with Dr. Jack Rogers, we have launched a CNS drug discovery initiative, and we are identifying potential sponsors to commercialize our recent invention on amyloid precursor protein (APP) mRNA blockers for treating Down’s syndrome and Alzheimer’s disease (AD). Further, I have identified and characterized the role of environmental stressors such as metal oxide nanoparticles in neuronal cell death using high content imaging technology, contemplating their potential link to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, given that nano-neurotoxicity is a very sensitive issue among both the scientific community and the public. Additionally, both independent component analysis (ICA)- and ant colony optimization-based algorithms have been applied to Alzheimer-related DNA microarray data analysis and gene order computation, respectively, for Alzheimer-associated gene expression clustering and potential biomarker identification. Moreover, Dr. Huang and his colleagues have developed an automatic ICA-based method coupled with Support Vector Machine (SVM) classifier that can differentiate AD and mild cognitive impairment (MCI) patients from age-matched healthy control subjects, using clinical MRI data. In addition, Dr. Huang has supervised four undergraduate, graduate and medical students, three technicians, and nine postdoctoral fellows over the years.
Susruthi Rajanala is a student in the 7 year BA/MD program at Boston University and will be starting medical school in the fall of 2016. Her interests include neurodegenerative diseases and DNA/RNA based therapies. She assists with western blots and cell assays as well as manuscript drafting and editing for the lab.
Conan Huang received his BS in Chemical Engineering from Brown University in May, 2014. He is currently a second year medical student at NYU School of Medicine. In the Neurochemistry Laboratory he contributed to the studies of the novel small molecule inhibitors of neurodegenerative disease genes including those for the potential treatment of Alzheimer’s disease
Bosco Tam is currently a medical student in the University of Hong Kong under the program of Bachelor of Medicine and Bachelor of Surgery Program (MBBS) a 6 year curriculum (2012-2018). “In the summer of 2012, I was very lucky to be accepted into Dr. Roger’s and Dr. Cahill’s laboratory in Massachusetts General Hospital to learn and help with their research on neurodegeneration and inflammation. It was a wonderful and stimulating experience and provided me a glimpse into one of the best medical research institutes in the world”.
Publications by Dr. Rogers: https://connects.catalyst.harvard.edu/Profiles/display/Person/47607
Publications by Dr. Cahill: https://connects.catalyst.harvard.edu/Profiles/display/Person/87371
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Contact either Dr. Jack Rogers, 617-726-8838 or Dr. Catherine Cahill, 617-643-4029 if you would like to inquire about philanthrophic contributions to help support this research.
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