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URMC-099 Combats Surgery-Induced Delirium, Cognitive Dysfunction in Preclinical Model of Orthopedic Surgery

Wednesday, November 6, 2019

URMC-099

Living microglia, genetically marked to glow green, in the cerebral cortex with magenta colored blood vessels from a mouse treated with URMC-099.

A new study published in the Journal of Neuroinflammation found that prophylactic treatment with URMC-099 -- a "broad spectrum" mixed-lineage kinase 3 inhibitor -- prevents neuroinflammation-associated cognitive impairment in a mouse model of orthopedic surgery-induced perioperative neurocognitive disorders (PND).

PND, a new term that encompasses postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder, is the most common complication after routine surgical procedures, particularly in the elderly. Following surgery, such as hip replacement or fracture repair, up to 50 percent of patients experience cognitive disturbances like anxiety, irritability, hallucinations, or panic attacks, which can lead to more serious complications down the line. Currently, there are no FDA-approved therapies to treat it.

Developed in the laboratory of Harris A. "Handy" Gelbard, M.D., Ph.D., director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, URMC-099 inhibits damaging innate immune responses that lead to inflammation in the brain and accompanying cognitive problems. Using animal models of diseases like HIV-1-associated neurocognitive disorders, Alzheimer's disease and multiple sclerosis, Gelbard has shown that the compound blocks enzymes called kinases (such as mixed lineage kinase type 3, or MLK3) that respond to inflammatory stressors inside and outside cells.

Gelbard and Niccolò Terrando, Ph.D., director of the Neuroinflammation and Cognitive Outcomes laboratory in the Department of Anesthesiology at Duke University Medical Center, used an orthopedic surgery mouse model that recapitulates features of clinical procedures such as a fracture repair or hip replacement, which are often associated with PND in frail subjects. In a pilot experiment, they treated one group of these mice with URMC-099 before and after surgery, and another group prior to surgery only. Gelbard and Terrando's teams, including first author Patrick Miller-Rhodes, a senior pre-doctoral student in the Neuroscience Graduate Program working in the Gelbard lab at URMC, measured the following:

  • How the surgery affected the central nervous system and the immune cells (microglia) that reside there was evaluated using stereology and microscopy.
  • Surgery-induced memory impairment was assessed using the "What-Where-When" and Memory Load Object Discrimination tasks.
  • The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry.
  • Long-term fracture healing was assessed in fracture callouses using micro-computerized tomography and histomorphometry analyses.
  • For additional details see the "Materials and Methods" section of the study

The team found that the surgery disrupted the blood brain barrier and activated microglia (a first line immune responder present in the inflamed brain), which led to impaired object place and identity discrimination when the mice were subject to the "What-Where-When" and Memory Load Object Discrimination tasks. Both URMC-099 dosing methods prevented the surgery-induced microgliosis (increase in the number of activated microglia) and cognitive impairment without affecting fracture healing.

"A major concern regarding the use of anti-inflammatory drugs for PND is whether they will affect fracture healing. We found that our preventive, time-limited treatment with URMC-099 didn't influence bone healing or long-term bone repair," said Gelbard and Terrando, professor of Neurology, Neuroscience, Microbiology and Immunology, and Pediatrics at URMC and associate professor of Anesthesiology at Duke University Medical Center, respectively. "These findings of improvement in cognition and normal fracture healing provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND."

"Right now we have nothing to treat this condition," said Mark A. Oldham, M.D., assistant professor in the department of Psychiatry at URMC who treats patients with PND. "We work hard to provide good medical care, including helping people sleep at night and making sure they are walking, eating and drinking, but it isn't clear that these efforts have any meaningful long-term impact."

According to Oldham, recent studies that track patients following an episode of PND show that many of them don't resolve completely, and that they have a new cognitive baseline after delirium.

"It is increasingly an accepted fact that after delirium, people have suffered some kind of neurological insult, which leaves them cognitively or functionally worse off than before the incident," he noted.

Next steps for the research include identifying definitive mechanisms for pain modulation, immune cell trafficking and neuro-immune characterization in PND. Gelbard and Terrando are tackling some of these questions with funds from the National Institutes of Health (RO1 AG057525). The current study was also funded by multiple grants from the NIH (P01MH64570, RO1 MH104147, RO1 AG057525 and F31 MH113504). The University of Rochester has four issued U.S. patents and multiple issued patents in foreign countries covering URMC-099.

Medical Student Gordon Wong presents at the annual URMC Medical School poster session

Monday, October 21, 2019

Georas nad Wong

Dr. Georas (left) and Gordon Wong

Medical Student Gordon Wong presented a poster at the annual URMC Medical School poster session, describing his summer research project. Gordon studied how protein kinase D regulates airway inflammation and epithelial barrier integrity in mouse models of airway inflammation and viral infections. He made some very exciting discoveries, working with graduate student Janelle Veazey, specifically elucidating how protein kinase D controls the recruitment of neutrophils to the lungs.

Leigh Wexler Graduates!

Friday, September 6, 2019

quiet time

Dr. Leigh Wexler and Dr. Portman (From Left)

Congratulations to Dr. Leigh Wexler, who successfully defended their thesis this week, earning a Ph.D. in Genetics from the GDSC program. Leigh's thesis research in the Portman Lab focused on the regulation of neuronal circuit function and behavior in the nematode C. elegans. It's been known for many years that males of this species tend to leave a food source to find mates, but that depriving males of food causes them to reprioritize feeding behavior over exploration. One important component of this behavioral flexibility is regulated chemosensory function. Well-fed males detect food poorly, partly due to low expression of a food-associated chemoreceptor called ODR-10, but food-deprived males upregulate ODR-10, increasing food attraction and decreasing food-leaving behavior. In contrast, hermaphrodites (the female equivalent in C. elegans) are strongly attracted to food and exhibit high levels of ODR-10 expression even when well-fed.

Leigh's research probed the mechanism by which ODR-10 expression is influenced by feeding status in males. They found that signals through two conserved pathways, involving the TGFβ-family ligand DAF-7 and the insulin-like (IIS) receptor DAF-2, are important for keeping ODR-10 expression low in well-fed males. Further, Leigh found that males in which the IIS pathway is constitutively active fail to upregulate ODR-10 when starved. Interestingly, the DAF-7 signal appears to act upstream of IIS, indicating that a cascade of neuroendocrine interactions is necessary for repressing ODR-10. And DAF-7 does not act as a sensor of the starved male's physiological state, but rather conveys information about the presence of food in the environment.

Together, Leigh's research demonstrates that C. elegans males assess their external state, rather than their metabolism, when deciding whether to take the risk of leaving food to find a mate, and that this occurs through a multistep neuroendocrine feedback loop. Leigh's work also provides important insights into how internal and external states are integrated by the nervous system to influence gene expression, neuronal circuit function, and behavior. This work will appear in an upcoming issue of Current Biology. We wish Leigh all the best as she set out to Boston, to start her post-doctoral career in the laboratory of Max Heiman at Harvard.

Janelle Veazey Receives Outstanding Student Mentor Award

Wednesday, September 4, 2019

Veazey

Janelle Veazey

Immunology Graduate Student Janelle Veazey received the Outstanding Student Mentor Award at the School of Medicine and Dentistry Convocation Ceremony on Wednesday, September 4th, Janelle was selected by the faculty of the Graduate Program in Microbiology & Immunology, in recognition of her outstanding commitment and dedication to mentoring undergraduate or graduate students. Congratulations Janelle!

Deb Fowell Authors Study on Immune Cell Navigation Systems

Tuesday, August 13, 2019

gaylo cover

When immune cells get recruited to infections, tumors, or other sites of inflammation they exit the blood stream and begin searching for the damage. But how they effectively traverse the body's tissue and home in on their targets is unclear. A new study led by Deborah Fowell, Ph.D. suggests that T cells have distinct navigation systems that help them pinpoint their targets.

Fowell's research team, based in the David H. Smith Center for Vaccine Biology and Immunology in the Department of Microbiology and Immunology made the discovery by visualizing the immune system in real time using intravital multiphoton microscopy. The technology allows you to look directly into the skin and observe the dynamic behavior of immune cells 'live.' Their findings were published earlier this month in the journal Immunity.

"We thought that locating the infection foci was a passive event for immune cells; that they used the tissue as a scaffold to weave their way through this complex matrix to get to their target," said Fowell, Dean's professor in the Department of Microbiology and Immunology. "We discovered that they are pre-programmed to respond to certain cues within the tissue microenvironment that help them find their targets more efficiently."

The team hopes that discovering these specialized programs for migration in tissues will provide new therapeutic targets that enable manipulation of the immune response in a disease-specific or tissue-specific fashion, rather than globally suppressing the immune system. Possibilities include boosting protective immunity in diseases where the immune system is inefficient, such as chronic infections and tumors, and limiting immunity in diseases that are exacerbated by the immune system, like autoimmunity and heart disease.

Hen Prizant, Ph.D., a postdoctoral fellow in Fowell's lab and Alison Gaylo-Moynihan, M.D., Ph.D., a former student in the lab are co-first authors. Graduate students Ninoshka R.J. Fernandes, Hannah Bell, Dillon C. Schrock, Tara Capece, Brandon Walling, and Christopher Anderson contributed to the study. Faculty members David Topham, Minsoo Kim, Alan Smrcka and James Miller are also authors.

Fowell credits the new finding to the power of NIH Program Project Grants (P01), which allow faculty, trainees and students to explore uncharted scientific territory and branch out among different disciplines. For example, the team reached across Elmwood Avenue to have conversations with astrophysicists and engineers on River Campus about how objects move through and are found in space. The P01 that funded the research was awarded to Fowell (PI) and Kim, Topham and Miller in 2014.

Supriya Mohile Headlines MSTP 19th Annual Retreat

Monday, August 12, 2019

retreat photo

The Medical Scientist Training Program's 19th Annual Retreat was held on August 9, 2019, at the Rochester Yacht Club. The retreat is an opportunity for the student body to gather to discuss science and welcome the incoming class. This year, the MSTP welcomed six new students: Maya Anand (Columbia University), Thomas Delgado (University of Florida), Svetlana Markova (Kharkiv National Medical University), Michael Meadow (UCLA), Gavin Piester (University of Rochester), and Victor Zhang (University of Rochester).

2019 MSTP Incoming Students

2019 Incoming Students

This year's Keynote address was given by Dr. Supriya Mohile, Professor of Medicine and Surgery at the University of Rochester, and was titled "Improving Care Delivery and Outcomes for Older Patients with Cancer and their Caregivers." Dr. Mohile highlighted the need for geriatric assessments in oncology to properly address concerns such as tolerability and toxicity of cancer treatments. She described the large clinical studies that are ongoing which demonstrate the feasibility of implementing geriatric assessments in oncology and stressed the need for all clinicians who treat elderly patients to use tools available to them to address concerns that are unique to this population.

The morning science session concluded with short talks by several current MSTP students. Second year medical student Emily Isenstein discussed her work on proprioceptive and visual integration in children with autism, Fara Tolibzoda Zakusilo (G2) discussed the role for the extracellular matrix in Alzheimer's disease, Jesse Wang (G3) spoke about the development of a digital medical scribe, Booyeon Han (G4) described her work to understand the tumor-draining lymph node in pancreas cancer, and Aimee Morris (M4) spoke about resting state functional connectivity in focal dystonia.

Following lunch, Kerry O'Banion, MSTP director, gave an update on curricular changes occurring in the medical school, which was followed by a presentation by students who attended the National MD/PhD Conference at Copper Mountain in July. New students were elected to the MSTP student council to end the afternoon. We look forward to another exciting year for the MSTP!

SMD's Aleta Anthony Named Director of Equity, Inclusion & Research Education Support

Friday, August 9, 2019

Aleta AnthonyThe Office for Graduate Education and Postdoctoral Affairs (GEPA) at the School of Medicine and Dentistry has announced the appointment of Aleta Anthony to the role of Director of Equity, Inclusion and Research Education Support.

The directorship is a newly-created position aligning with the University of Rochester and the Medical Center's broader mission to support equity and inclusion through strategic efforts, organizational programming, and inclusion initiatives. As director, Aleta will provide leadership and direction to GEPA to foster an environment where all members of the GEPA community are supported and acknowledged for diverse backgrounds and experiences.

In a commitment to promoting equity and inclusion for students and postdocs, Richard Libby, Ph.D., who is senior associate dean for GEPA, worked with the University of Rochester Medical Center's Office for Inclusion and Culture to create Anthony's new role.

Anthony joined the School of Medicine and Dentistry in 2017 as the director of graduate enrollment for Ph.D., master's, and certificate programs. In addition to her new role leading GEPA's equity and inclusion efforts, she will continue her work building and enhancing recruitment strategy for the school's biomedical sciences and health sciences graduate programs.

Single Brain Region is Key to Assessing the Impact of Repetitive Head Hits, Concussions

Wednesday, August 7, 2019

While a brain injury can be difficult to locate, new research identifies a single region of the brain that can be used to examine the impact of a concussion or repeated hits to the head.

The finding, published today in Science Advances, also supports the emerging idea that traumatic brain injury is not limited to people who sustain a concussion; it can result from repetitive head hits that are clinically silent--those that do not produce the visible signs or symptoms of a concussion. These subconcussive hits have been increasingly recognized as a potential threat to long-term brain health and as a possible cause of chronic traumatic encephalopathy (CTE).

Jeffrey Bazarian, M.D., M.P.H., professor of Emergency Medicine, Neurology, Neurosurgery and Public Health Sciences at the University of Rochester Medical Center and a co-author of the study says that the location of a brain injury varies widely from person to person. This is a major obstacle for physicians trying to diagnose brain injury using imaging techniques.

"This study is important because we found that no matter where the head gets hit, the force is translated into a single region of the brain known as the midbrain," noted Bazarian, who treats concussion patients and conducts research related to traumatic brain injury. "Midbrain imaging might be a way in the future to diagnose injury from a single concussive head hit, as well as from repetitive sub-concussive head hits."

University of Rochester fourth-year medical student Adnan Hirad, Ph.D., the first author of the research added, "Our findings do not dispute the fact that head-injury effects are distributed throughout the brain, but the midbrain may serve as a 'canary in a coal mine' in terms of identifying damage. From this study we know that the midbrain region, which is linked to brain functions often affected by a concussion, is the place to look to identify the impact of clinically defined concussions with visible symptoms and silent brain injuries that can't be observed simply by looking at or behaviorally testing a player, on or off the field."

Read More: Single Brain Region is Key to Assessing the Impact of Repetitive Head Hits, Concussions

Congratulations MJ

Thursday, July 11, 2019

Bone Quality Matrix DiagramAfter successfully defending his thesis, MJ has completed the PhD portion of his MD/PhD studies. MJ's studies investigated the genetic basis of bone-matrix quality, an underappreciated property of bone that contributes significantly to bone strength and is of great clinical importance for understanding of bone pathology such as osteoporosis. MJ used both a classical population genetics approach as well as a systems genetics approach, and found that bone matrix characteristics such as morphology and matrix composition are indeed inheritable properties. In addition, using an estrogen-deficient model of post-menopausal bone loss, he was able to identify gene networks that may play an important role in osteoporosis. His results suggest that bone matrix quality is influenced by genetics and participates in maintaining tissue-level mechanical properties. Furthermore, identifying putative regulatory genes is clinically significant as they are presumptive targets for developing novel therapeutics. During his thesis work, MJ was the recipient of a CTSI Pilot Trainee Grant and scored a fundable F31 predoctoral fellowship from NIAMS. With his GDSC doctorate in hand MJ will return to medical school to obtain his M.D. Best of luck in your future ventures, MJ!!

Scott Friedland Defends Thesis

Thursday, July 11, 2019

This week M.D./Ph.D. student Scott Friedland defended his doctoral thesis. Arriving at the GDSC in 2014, Scott pursued his Ph.D. under the mentorship of Dr. Aram Hezel. As a student Scott was granted travel awards to a national physician scientist conference and selective course at Cold Spring Harbor Labs. His thesis, titled Arid1a, a subunit of the SWI/SNF chromatin remodeling complex, is a barrier to KrasG12D-driven tumorigenesis, studied the role of SWI/SNF, a chromatin remodeling complex, in pancreatic function and disease, which has implications for the fields of cancer and developmental biology. These findings may, in time, impact the treatment of diseases such as pancreatitis and pancreatic cancer. Scott will be reinitiating his medical education alongside the class of 2021 here at the University of Rochester School of Medicine, and is interested in pursuing a career as an oncologist and cancer researcher. Congratulations Dr. Scott Carl Friedland!

Scott Friedland Defends Thesis | Scott at Poster Session

Study Points to Stabilization of TRAF3 Protein to Fight Age-Related Bone Loss

Wednesday, June 26, 2019

A new study led by Brendan Boyce, M.B.Ch.B.., professor of Pathology & Laboratory Medicine and the Center for Musculoskeletal Research and Zhenqiang Yao, MD., Ph.D., assistant professor of Pathology & Laboratory Medicine suggests that age-related osteoporosis could be prevented or treated through pharmacologic stabilization of the protein, TNF receptor-associated factor 3 (TRAF3).

The collaborative study was published in Nature Communications after five years of work by Boyce and fellow URMC researchers who note the need to better understand the mechanisms through which osteoporosis occurs in order to develop new drugs that can be given to help prevent or reverse the disease.

The study notes that the process by which young, healthy peoples' bones are naturally rebuilt, deteriorates as people age or go through menopause. Increased inflammation, or inflammaging, leads to an increase in bone-degrading osteoclast cells and a reduction in bone-forming osteoblasts, resulting in osteoporosis.

Existing treatments that prevent bone destruction offer long term solutions, but many patients are reluctant to take them because they fear side effects of the drugs, while bone forming drugs can be administered only for short periods to help patients suffering from chronic osteoporosis.

The paper shows that the protein, TGF-beta, which is released in increasing amounts from bone during aging, causes breakdown of TRAF3 in osteoblast precursor mesenchymal progenitor cells. This leads to a reduction in the number of osteoblasts and less bone repair and indirectly to increased numbers of osteoclasts and more bone destruction.

By stabilizing TRAF3 levels in bone cells through new drugs, the authors provide a novel mechanism for how treatments may offer a more long-term solution for patients. This is especially crucial as more people live longer and are exposed to a greater risk of fractures and early death.

Lemonade Stand Supports Efforts to Cure Childhood Cancer

Friday, June 21, 2019

For the 10th year in a row, Danielle Benoit, associate professor of biomedical engineering, and mentees from her lab will hold their fundraiser in support of Alex's Lemonade Stand Foundation and its efforts to cure childhood cancer. You can donate online or drop by the lab's lemonade stand from 10 a.m. to 1 p.m. Saturday, June 22, at the Rochester Public Market, 280 Union Street North or from 9 a.m. to 1 p.m. Sunday, June 23, at the Brighton Farmers Market,1150 Winton Road South.

Liwei Wang, Ph.D., Graduate of the Cellular and Molecular Pharmacology and Physiology PhD Program Wins the Fenn Award for Best Thesis

Thursday, June 20, 2019

Drs. Libby, Yule and Wang with the Fenn AwardLiwei Wang, Ph.D. Graduate of the Cellular and Molecular Pharmacology and Physiology PhD Program won the Fenn Award for best thesis, the award was presented at the 2019 Commencement Dinner by Richard Libby, Senior Associate Dean for Graduate Education and Postdoctoral Affairs following an introduction from Dr. Wang's faculty mentor, Dr. David Yule.

The award was for Dr. Wang's thesis, entitled "Region-specific Proteolysis Differentially Regulates Inositol 1,4,5-trisphosphate Receptor Activity " Dr. Wang is currently a Postdoctoral Fellow in the laboratory of Prof. Stefan Feske at NYU, Langone Medical School. His current research involves investigating the role of ion channels in immunological tolerance and immunity.

About the Award

Dr. Wallace Fenn was a Professor of Physiology at the University of Rochester School of Medicine and Dentistry from 1924 to 1961. He served as the Chairperson of the Department of Physiology from 1924 to 1959 and thereafter until his death in 1971, he was appointed by the University to the position of Distinguished University Professor of Physiology. As well, Dr. Fenn served as the Associate Dean of Graduate Studies from 1957 to 1959.

To read more regarding this award, please visit the department of Biochemistry and Biophysics website.

A Graphic Design Revolution For Scientific Conference Posters

Tuesday, June 18, 2019

"Other templates didn't necessarily ask you to think about what you were putting on them because they allowed it all," says Derek Crowe, a PhD student in biomedical genetics in Hucky Land's lab with a former career in visual communication and design, "In order to use Mike's layout though, my hand is forced."

With the new template, scientists need to think about their core message, but some people have a difficult time figuring out how to do that, or how to use visuals to present their message. Without proper science communication training, even a better poster template doesn't work.

Crowe has taken matters into his own hands. Not only does he teach a course on visual communication for scientists at the University of Rochester, but he also shared his poster design tips online. In a nod to Morrison's "better poster", Crowe's is a "butter poster". He provides step by step instructions on how to organize the poster, and how to think about the content in a visual way.

"Like the graphic novel did for literature, visual languages have the power to add more dimensions to scientific storytelling," says Crowe, "I'm excited to see what happens as the greater science community begins to take advantage of well-established visual storytelling tools."

Read More: A Graphic Design Revolution For Scientific Conference Posters

Romeo Blanc Receives Multiple Awards From the International Society for Stem Cell Research (ISSCR)

Thursday, June 13, 2019

Romeo

Romeo Blanc postdoctoral fellow in the Chakkalakal Lab was the recent recipient of the Podium presentation, Travel award, and Merit Awards from the International Society for Stem Cell Research (ISSCR) for the upcoming annual meeting in Los Angeles CA, June 26 -- June 30, 2019.

The first award, called Travel Award, came from the ISSCR itself and covers registration and/or cash award. The second award, called Abstract Merit Award is made to highlight some outstanding selected abstract which is chosen by ISSCR as well.

Congratulations Romeo!

CMPP Students Host Guest Speaker Dr. Ehsan Sarafraz-Yazdi

Tuesday, June 11, 2019

To fortify the involvement of graduate students in academic affairs, the Department of Pharmacology and Physiology (CMPP) hosted student nominated guest speaker: Dr. Ehsan Sarafraz-Yazdi, Ph.D., M.P.H., Founder and CEO of NomoCan Pharmaceuticals, LLC. Dr. Yazdi was nominated by PhD candidate Edward Ayoub and chosen by CMPP graduate students to spend a day at URMC. During his visit, Dr. Yazdi connected with faculty and students, and presented a seminar highlighting a new microfluidic system to study anti-cancer drug responses ex-vivo. Dr. Yazdi also shared his vision and inspiration to start his own pharmaceutical company at a URBEST Career Story hosted by Dr. Tracey Baas. CMPP will continue to host a student-nominated guest speaker annually.

Left to right: Lily Cisco, Dr. Ehsan Yazdi, Edward Ayoub, Kai Ting Huang, Alexander Milliken, Matthew Rook

Left to right: Lily Cisco, Dr. Ehsan Yazdi, Edward Ayoub, Kai Ting Huang, Alexander Milliken, Matthew Rook

Upcoming Thesis Defenses

Friday, June 7, 2019

Rebeckah Burke, chemistry, "Colloidal Semiconductor Nanocrystals for Photocatalytic Proton Reduction." 10 a.m. June 11, 2019. 108 Goergen Hall. Advisor: Todd Krauss.

Philipp Birklbauer, mathematics, "Theoretical and Computational Explorations in Vector Spaces Over Finite Fields." 2:30 p.m. June 12, 2019. Hylan 1106A. Advisor: Alex Iosevich.

Molly McCann, epidemiology, "Degree of Bystander-Patient Relationship and Prehospital and Emergency Department Care for Opioid Overdose." 10 a.m. June 14, 2019. Helen Wood Hall | 1W 502. Advisor: Todd Jusko.

Jie Luo, biology, "The Role of Androgen Receptor in Different Prostate Cancer Therapies." 12:30 p.m. June 14, 2019. Room 2-6424 Medical Center. Advisor: Chawnshang Chang.

GDSC Student, Tom O’Connor Earns First Place in 2019 Sharing Your Science in A Social World Contest.

Monday, June 3, 2019