After a few snow storms delays, BUSM's second year medical students finally...
By Lisa Brown
SIG Pre-submission Process
The Shared Instrument Grant (SIG) program encourages applications from groups of NIH-sponsored investigators to purchase or upgrade a single item of expensive, specialized, commercially available instruments or integrated systems that cost at least $50,000. Types of instruments supported include, but are not limited to: X-ray diffraction systems, nuclear magnetic resonance (NMR) and mass spectrometers, DNA and protein sequencers, biosensors, electron and confocal microscopes, cell-sorters and biomedical imagers. See RFA here: http://grants.nih.gov/grants/guide/pa-files/PAR-15-088.html
The office of the Associate Dean for Research, BUSM will facilitate an internal SIG pre-submission process to foster collaborative proposals and increase the success rate for the University. This pre-submission process requires that applicants fill out an online form designed inform Dr. Antman, BUSM Dean and BUMC Provost of your interest in applying for an S10 Shared Instrumentation Grant.
The proposals will be routed to the Core Advisory Committee, who will assist the Associate Dean for Research, BUSM and the Provost with evaluating scientific merit and ensuring that highly-rated applications receive the appropriate level of institutional support to make them most competitive.
This process will:
- Identify the necessary level of institutional support needed for a competitive application.
- Identify any potential space and renovation needs ahead of the application.
- Help obtain access to equipment, or equipment loans, in order to generate additional data to strengthen the application if needed.
- Alert other members of the research community who may be important additions to the users group, and ensure transparency of the SIG process.
- Ensure that we do not have competing applications for similar equipment.
This process is not intended to prevent submission of applications, but to recognize that when multiple applications are being submitted, it may not be possible to centrally support all of them at a competitive level from the Provost’s or the Deans’ resources, providing the opportunity to identify alternative sources of funding.
If you are considering submitting a SIG in 2015, please fill out the SIG pre-submission online form as soon as possible. The internal submission deadline university-wide is March 9.
Members of the Medical Campus are invited to the Feb. 6 Cancer-focused Seminar Series (CFSS). The goal of the CFSS is to promote interaction and collaboration of cancer researchers across the Medical and Charles River campuses. Three talks will be presented at this seminar.
- Tracy Battaglia, MD, MPH, Battaglia Lab, “Repairing the Disconnect: Optimizing Cancer Care Delivery Through Patient Centered Research”
- Charina Ortega, Dominguez Lab, “Mining CK2 in Cancer”
- Kevin Chandler, PhD, Costello Lab, “Studying Posttranslational Modifications of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) in Tumor Angiogenesis
What: Cancer-focused Seminar Series
When: Friday, Feb. 6, Noon-1:15 p.m.
Where: BUSM Instructional Building, L-110
Mark your calendar for future seminars March 6, April 3, May 1. All future seminars will take place noon-1:15 p.m. in Bakst Auditorium.
Mikel Garcia-Marcos, PhD, assistant professor in the department of biochemistry was recently awarded two grants from the National Institutes of Health-National Institute of General Medical Sciences. The grants, totaling approximately $2.5 million, will fund his two projects “Alternative mechanisms of G protein signaling” and “Identification of chemical probes that specifically target the GIV-Gi interface.”
Cells composing the different tissues and organs of the human body constantly perceive and respond to environmental signals to function normally. A vast array of human diseases including cancer, birth defects, diabetes or neurodegeneration appears when this process goes out of control. Although the molecular machinery that controls how cells perceive and respond to environmental cues is extremely complex, a group of molecules called G proteins play a pivotal role. Essentially, they work as “on/off” switches that control the flow of information from the environment into the cells.
The Garcia-Marcos lab is interested in dissecting new molecular mechanisms by which G proteins are regulated and how these will impact disease and therapeutics. “G protein signaling already represents the major target for currently marketed drugs. Revealing new ways by which they are regulated will open new avenues for therapeutic intervention by targeting this important mechanism of cell control,” explained Garcia-Marcos.
In his first project, Garcia-Marcos plans to identify and characterize a whole new family of G protein regulators–some which have already been shown to play a role in controlling cancer progression and embryonic development. “By identifying new ways of G protein regulation in health and disease we hope to understand better a fundamental biological process and discover promising therapeutic targets,” he added. The goal of his second project is to identify drugs to inhibit one of the newly identified G protein regulators, which they have found to be an inducer of cancer metastasis, the cause of more than 90 percent of cancer-related deaths. “This is the essence of what we do. We believe that focusing our research on basic science is bound to eventually deliver the so-called translational impact.”
Garcia-Marcos completed his PhD in European labs located in the Basque Country and Belgium. He joined BUSM as an assistant professor in 2012 after completing a five-year postdoctoral training at University of California, San Diego. He is also funded by a junior investigator award from the American Cancer Society.
Boston University School of Medicine has developed an affiliation with Northern California Kaiser Permanente to offer two new clinical clerkship sites for our third-year medical students.
Beginning in May 2015, 12 third-year students will begin their clerkships at Kaiser Permanente Medical Centers in San Jose and Santa Clara. After an orientation with their classmates in Boston, six will stay for a full year, while six will stay for six months. Students will rotate in family medicine, OB/GYN, internal medicine, psychiatry and neurology at the San Jose site and in pediatrics, surgery, radiology and psychiatry at the Santa Clara site. Although this program is new for BU, Kaiser has a strong and well-established medical education framework that includes students from Stanford, UC-San Francisco, UC-Davis and Drexel.
In addition to an excellent clinical experience, the Kaiser Campus Third-Year Curriculum Program will expose students to Kaiser’s healthcare technology, preventive medicine and progressive healthcare delivery model. Students will participate in quality improvement training programs, master their electronic health system, and develop their own quality improvement projects.
Kaiser has revolutionized health care and health-care technology, providing more immediate and responsive patient care. A leader in patient safety and quality improvement, the Kaiser system has been the model for the future of medicine. Their focus on preventive care and an outpatient-centered care model reduces hospital admissions and testing.
“We are delighted to offer our students the opportunity to work in another innovative and evidenced-based system that is committed to high-value, high-quality medical care,” said Karen Antman, MD, BUSM dean and provost of the BU Medical Campus.
Despite the distance from Boston campus, students will receive uniform didactic instruction. Program Manager Monica Parker-James is coordinating the online educational experiences. Recorded lectures can be reviewed at the student’s convenience. The students also will be able to participate in live small-group discussions and case vignettes with Microsoft Lync access.
Microsoft Lync is a platform for unified communications including online meetings, instant messaging, audio and video calls, availability info and sharing capabilities.
Dr. Harley Goldberg, who has a long history of service in the Kaiser system and is involved in quality evaluations at San Jose, will coordinate the training and supervision of our students in California. He will work with students via video conferencing prior to June and will orient and mentor the students during their time in the Kaiser facilities. He has worked closely with the BUSM Kaiser Committee and clerkship directors to provide a seamless transition for the students.
Assistant Dean Paige Curran in the Office of Student Affairs will monitor student mental and physical health and support academic and career development through online communication and quarterly visits to California.
The BUSM students will have faculty support while in California and many will also be close to family and friends. In addition, we are planning a California BUSM alumni network for additional student support, mentoring and career development. Several alumni have already expressed interest, including Veronica Santini, BUSM class of 2000, an assistant professor of neurology at Stanford.
“We are impressed by how vested our counterparts in California are in making this a successful partnership,” said Anna Hohler, MD, assistant dean of academic affairs at BUSM. “This collaboration is a win-win. Kaiser will work with students who are smart, dedicated and professional. Our students will train in a leading health care system that shares our commitment to high-quality medical education, devotion to diverse patient populations and a vision for excellence in health care. We are thrilled to be able to offer this opportunity to our students.”
Deborah A. Frank, MD, BUSM inaugural Professor in Child Health and Well-Being, Pediatrics, has been named to the National Commission on Hunger by the U.S.Congress. Frank is director of the Grow Clinic for Children at Boston Medical Center (BMC) and founder and principal investigator of Children’s HealthWatch, a network of pediatric and public health researchers working to improve child health. A highly respected national authority, she has testified before both the United States and Massachusetts legislatures on the growing national problem of hunger and its effects on children. Learn more at https://hungercommission.rti.org/.
A recent study may help begin to explain how cancer develops though the abnormal turning on and off of genes. Researchers have discovered that the increase of methyl tags in cancer cells is due to highly efficient DNA methyl transferase 1 (DNMT1) enzymes found in these cells. The findings appear in the Journal of Proteomics and Bioinformatics.
Both plants and animals have genetic machinery that modifies the information and function of their genomes without actually changing their genetic code. This modification process is known as “epigenetics.” One of the best studied of these epigenetic processes involves the chemical tagging of DNA nucleotides across the genome using methyl groups. These “methyl tags” are attached to cytosine nucleotides in specific patterns around genes and other expressed sequences by a specialized group of enzymes called methyltransferases.
Genes that are expressed and turned into proteins are free of “methyl” tags, but when such methyl tags attach to DNA, gene expression is turned off. “Whether methyl tags are added to genes varies during normal development and during the development of diseases like cancer, and understanding these processes is currently a major topic of research,” explained corresponding author Sibaji Sarkar, PhD, instructor of medicine at Boston University School of Medicine (BUSM). According to Sarkar it was previously discovered that cancer cells have more methyl tags than normal cells and level of the enzyme which adds the tag, DNA methyl transferase1 (DNMT1) is also higher, but no one knew that both increases are not proportional.
The researchers focused on two types of cells – cancer cells and normal healthy cells. For each cell type, they used mathematical Hill equation to determine whether the methylation status (methyl tags present as compared to those which were absent) of eight selected genes correlated with the amount of DNA methyl transferase1 (DNMT1) enzyme present in the cells. They found that the enzyme that adds these tags (DNMT1) worked more efficiently in genes which are silenced in cancer cells as compared with normal healthy cells. Interestingly, the enzyme did not work efficiently with the genes which are not silenced by methylation in cancer cells. This increase in enzyme activity is called allostericity and it is observed in many cellular processes including addition of oxygen to hemoglobin to carry oxygen efficiently. The outstanding mystery which remains to be solved is, how this enzyme selectively chooses some genes to efficiently methylate.
“Since this highly efficient DNMT1 enzyme can promote cancer development, using a drug that inhibits this allosteric increase in enzyme activity may someday be beneficial for cancer treatment, because it will target the super active methylation process in cancer cells. We are developing a combination therapy that uses this type of epigenetic drugs in combination with other more traditional drugs, and researchers have shown that such treatments are effective and able to reduce cancer relapse,” he said. The idea behind the addition of epigenetic drugs in combination therapy is to make cancer cells susceptible and possibly kill cancer progenitor cells and drug resistance cancer cells.
Sarkar and his colleagues believe these findings begin to clarify how the regulation of DNMT1 impacts the normal and abnormal addition of methyl tags, and thus, gene transcription in general. “Hopefully, through this and future work, we will discover the molecular mechanisms that lead to differential silencing and expression of genes during human development from embryogenesis and the aberration of this process in many diseases including cancer development. This knowledge will hopefully develop methods of counteracting these mechanisms and treating cancer,” he added. The discovery that DNMT1 efficiently methylate selective genes brings us one step closer to the idea of “on” and “off” switch of cancer development. Recent studies have shown that genes are transcriptionally silenced by the creation of an insulated area, which regulate enhancer and transcription factor interactions. The formation and deformation of these areas in development and disease conditions including cancer possibly are regulated by this highly efficient methylation mechanism.
Also contributing to this study were first author Eric Samorodnitsky, PhD from Ohio State University, Boston University student Emily Ghosh and Sahana Mazumder, PhD from Rammohan College, University of Kolkata.
Partial funding of Sarkar’s laboratory work was provided by a grant from the American Cancer Society.
The identification of genetic variants that influence the structure of the brain may provide insight into the causes of variability in human brain development. The findings, which appear this week in the journal Nature, may also help determine the genetic processes that underlie neuropsychiatric diseases.
Portions of the human brain known as the subcortical regions are involved in functions associated with movement, learning, memory and motivation; alterations to the structure of these regions can lead to abnormal behavior and disease. To investigate how common genetic variants affect the structure of these brain regions, a worldwide group of researchers including those from Boston University School of Medicine (BUSM) analyzed genetic data and MRI scans collected from 30,717 individuals. They found a number of genetic variants that influence the volume of subcortical brain structures, and many of these variants seem to exert their effects through known developmental processes. One genetic variant found to be linked to changes in the volume of the hippocampus — a key region involved in learning and memory — is also known to be associated with schizophrenia.
The neurology working group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium is led by Sudha Seshadri, MD, a professor of neurology at BUSM and a senior investigator at the Framingham Heart Study. “This is another example of the wide range of new scientific discoveries that continue to emerge from the invaluable Framingham Heart Study cohort as well as the many diverse international collaborations BUSM researchers lead and participate in,” said Seshadri.
The study is a collaboration involving 30,000 participants and investigators from Australia, the U.S., Europe and Asia.
Deeper understanding of telomeres may lead to targeted cancer treatments
By a quirk of biology, every time an adult cell divides, a bit of DNA gets lopped off the end of the double helix. This seems like a recipe for disaster—imagine a crazed librarian ripping the last chapter off a book every time it got checked out. Soon, the book would be useless. So would truncated DNA, if not for structures called telomeres, long sequences of repetitive base pairs—the same meaningless TTAGGG over and over—that cap each end of our DNA. Every time a cell divides, it’s a bit of telomere that gets chopped off, rather than vital genes.
But biologists have long understood telomeres to be a double-edged sword. When they get too short, cells stop dividing. We see this as aging: hair turns gray, skin sags. But some cells are able to keep their telomeres long, effectively becoming immortal and dividing forever. Sometimes, the immortal cells become a cancer.
Now, scientists led by Rachel L. Flynn, a Boston University School of Medicine (MED) assistant professor of pharmacology and experimental therapeutics and medicine, have found a new way to kill certain cancers by targeting mechanisms of telomere elongation. The research, funded by the National Institutes of Health, the Foster Foundation, and the Karin Grunebaum Cancer Research Foundation, and published in the January 15, 2015, issue of Science, may lead to new therapies for certain rare and deadly cancers that often appear in children.
Cells that are able to lengthen their telomeres, and thereby divide indefinitely, use two known methods to do so. The more common is to use an enzyme called telomerase, which is active in embryonic stem cells but repressed as cells become specialized. The less common method, and the one Flynn studies, is called ALT, for alternative lengthening of telomeres. The ALT pathway is most prevalent in certain cancers, including pediatric osteosarcoma, a bone cancer, and glioblastoma, a type of brain cancer.
“In terms of the possible clinical applications, this research could be a game changer,” says Karen Antman, MD, provost of BU Medical Campus and dean of Boston University School of Medicine. “This exciting finding could allow us to target any cancer that uses the ALT pathway to maintain telomeres. Such cancers are often resistant to common treatment options and have a poor prognosis.”
The ALT pathway, though discovered almost two decades ago, is still poorly understood, says Flynn. “We know that ALT is a mechanism that relies on recombination—one telomere basically hijacks another and uses it to replicate and elongate itself,” she says. “But we didn’t know how the pathway was maintained until now.”
Flynn’s paper suggests how cancer cells may be able to maintain the ALT pathway—by depending on an enzyme called ATR kinase. This enzyme is what’s known as a “master regulator,” says Flynn. In a normal cell, it recognizes DNA damage when a cell is preparing to divide, and leads to either DNA repair or cell death. ALT cancer cells are constantly undergoing DNA repair at the telomere and are more reliant on ATR kinase activity than other cancer cells. Therefore, ATR promotes immortality by helping telomere elongation. Attack this enzyme, says Flynn, and you stop the cancer cell in its tracks.
“When you take ATR kinase out of the picture, it shuts down a whole chain of events,” says Flynn. “The cancer cell tries to promote telomere elongation, but it can’t, and the cell dies.”
There are several drugs already on the market that act as ATR kinase inhibitors, but none are used individually to treat these types of cancers. “The cool thing about these drugs is that the cancer cells actually die incredibly fast as opposed to just slowing down cell growth,” Flynn says. She also notes that since the drugs only affect cancer cells using the ALT pathway, normal cells should be left unharmed.
Flynn’s next step is to get the existing drugs into clinical testing for targeted use. She is working with a group at Massachusetts General Hospital who will test it on mice with glioblastomas. Eventually, she hopes, her work will lead to a new treatment for these deadly diseases.
“The dream is that this research will eventually give kids with devastating cancers an option for individualized treatment, something that will hopefully improve outcomes,” says Flynn.
This BU Today article was written by Barbara Moran. She can be reached at email@example.com.
A version of this story was originally published in BU Research.
Jan. 26 Exploring the Role of Social and Cultural Determinants Influencing Latino HIV and Substance Abuse Health Disparities
BU Medical Campus faculty, residents and PhD students are invited to a colloquium sponsored by the BU School of Social Work. Join Mario De La Rosa, PhD, Professor at Florida International University, Miami as he discusses “Exploring the Role of Social and Cultural Determinants Influencing Latino HIV and Substance Abuse Health Disparities” on Monday, Jan. 26 at 10:45 a.m. Dr. De La Rosa is a candidate for the inaugural Director of the Center for Innovation in Social Work and Health. A luncheon will immediately follow the colloquium, RSVP required by Jan. 22 to firstname.lastname@example.org
- “Exploring the Role of Social and Cultural Determinants Influencing Latino HIV and Substance Abuse Health Disparities”
- Mario De La Rosa, PhD, Professor at Florida International University, Miami
- Colloquium: Monday, Jan. 26, 10:45 a.m.
- Hiebert Lounge, BUSM Instructional Building
- Luncheon following colloquium, RSVP required by Jan. 22, email@example.com
Obesity-linked diabetes is a growing public health problem and contributes to cardiovascular disease, the most prevalent cause of death in the U.S. High plasma concentrations fatty acids derived from food intake and excess fat stores and high concentrations of glucose from diet are hallmarks of diabetes. Increasing attention has been directed to fatty acids and their multiple pathophysiological effects.
The plasma membrane receptor CD36 is a key protein that plays central roles in obesity and type 2 diabetes. It binds both fatty acids and oxidized low density lipoprotein (LDL), which has been implicated in promotion of atherosclerosis. However, the mechanistic roles of CD36 are complex and have remained elusive.
In a new study published in the Journal of Biological Chemistry, a research group led by James A. Hamilton, PhD, professor of Physiology, Biophysics and Radiology at Boston University School of Medicine, applied novel methods to detect binding of fatty acids to CD36 and their effect on internalization of oxidized LDL. Although other research groups have characterized a fatty acid binding site on CD36 and postulated CD36 to be a gatekeeper for fatty acid entry into cells, the Hamilton lab previously found that CD36 did not increase fatty acid translocation across the plasma membrane.
In the current study all of the common dietary fatty acid types (saturated, unsaturated, trans and polyunsaturated) were shown by a new assay to bind to CD36 at levels greater than expected for a single binding site characterized in previous studies. In cells with CD36 present in the plasma membrane, all of the fatty acids also enhanced oxidized LDL uptake, except for the fish oil fatty acid DHA. This current study adds to the possible mechanisms for fish oil benefits that are now widely recognized.
“Since obesity and type 2 diabetes are characterized by high plasma levels of fatty acids, the demonstrated enhancement of oxLDL uptake by increases in common dietary fatty acids may contribute to the pathophysiology of these diseases. Furthermore, our new results provided a link between fatty acids, CD36, and atherosclerosis and new drugs can be designed that target the exact mechanism more precisely.” added Hamilton.
The work was supported by a grant from the American Diabetes Association. The study’s co-authors are Anthony Jay, Alex Chen, Justin Hung, and Miguel Paz.