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Studies Led by Douglas Portman Examine Nervous System Changes During Puberty

Tuesday, July 9, 2019

Very little is known about how the onset of puberty is controlled in humans, but the discovery of a new gene in the roundworm C. elegans could be the "missing link" that determines when it’s time to make this juvenile-to-adult transition. Two genes, LIN28and MKRN3, are known to be associated with precocious puberty in humans, where juveniles as young as six may start developing adult features. These genes are found in all animals, including C. elegans, in which they also control the juvenile-to-adult transition. Until the new discovery, it was unclear how these two genes are connected.

The more obvious signs of the transition of juvenile-to-adult tend to be external—body morphology, matured genitalia—but nervous system changes are also happening at the same time. In humans, the maturation of the brain during adolescence is associated with increased vulnerability to a variety of neuropsychiatric disorders, so a better understanding of these processes is important for understanding mental health as well as basic neurobiology.

Two new studies in the labs of Douglas Portman, Ph.D. at the University of Rochester Medical Center and David Fitch at New York University, published in Developmental Cell and eLife, identified a new developmental timing mechanism involving a long non-coding RNA in the microscopic roundworm C. elegans. Their research revealed a surprising new molecular mechanism that controls the timing of sex-specific changes in body shape, the maturation of neural circuits, and behavior.

C. elegans has long been used by researchers to understand fundamental mechanisms in biology. Many of the discoveries made using these worms apply throughout the animal kingdom and this research has led to a broader understanding of human biology. In fact, three Nobel Prizes in medicine and chemistry have been awarded for discoveries involving C. elegans.  

The researchers identified a new gene that, when disrupted, delays the transition from the juvenile to the adult stage. Surprisingly, this gene, called lep-5, does not act as a protein, as most genes do. Instead, it functions as a long non-coding RNA (lncRNA), a recently discovered class of genes whose functions remain largely mysterious. The team observed that this lncRNA is important for promoting the juvenile-to-adult transition by directly interacting with LIN-28 and LEP-2, a C. elegans gene similar to MKRN3. Because the human versions of LEP-2 and LIN-28 are both involved in the timing of puberty, the new research suggests that a yet-to-be-discovered lncRNA might be essential to this process in humans as well.

Read More: Studies Led by Douglas Portman Examine Nervous System Changes During Puberty

Handy Gelbard Honored for Pediatric HIV/AIDS Research

Wednesday, April 17, 2019

Harris Gelbard

Handy Gelbard, M.D., Ph.D., professor and director of the Center for Neurotherapeutics Discovery at URMC, is the 2019-2020 recipient of the Herman and Gertrude Silver Award, which honors individuals who have made significant contributions in the field of pediatric HIV and AIDS. The award is given by the Children’s Hospital of Philadelphia (CHOP) and the Department of Pediatrics of the Perelman School of Medicine at the University of Pennsylvania. Past award winners include a Nobel laureate and HIV investigators from leading academic institutions, the National Institutes of Health (including the current directors of the Office of AIDS Research and the National Institute of Allergy and Infectious Diseases), and the Centers for Disease Control and Prevention.

For the past 10 years Gelbard’s lab has been developing a compound called URMC-099, which dampens inflammation and has shown promise in reversing the neurological problems associated with HIV. Children with HIV who are taking combination antiretroviral therapies are extremely vulnerable to inflammation; the developing nervous system is of particular concern, as inflammation in the brain can lead to major cognitive problems.

The possibility of a new class of therapies that reduces the burden of neuroinflammation and supports normal synaptic architecture (the basis for learning and memory) offers considerable hope for children that are saddled with the unwanted burden of HIV, despite effective control of the virus.

Gelbard believes the path forward for URMC-099 as an adjunct agent for children living with HIV and neurologic disease will likely involve combination therapy with next generation antiretroviral agents. This is a priority in resource-limited settings such as Africa, and Gelbard is working with David Bearden, M.D., assistant professor in the division of Child Neurology at URMC to help advance uses for URMC-099 in pediatric patients there. Bearden’s work is supported by a National Institute of Neurological Disorders and Stroke grant to Gretchen Birbeck, M.D., M.P.H., professor of Neurology and Michael Potchen, M.D., professor of Imaging Sciences. The work is also supported by the University of Rochester Center for AIDS Research.

Gelbard will receive the Silver Award in November during a two-day symposium at CHOP. He will present pediatric grand rounds describing his progress in inventing the class of compounds spearheaded by URMC-099 and its role in treating pediatric and adult HIV infection and its complications. He’ll also give a seminar on current and future developments related to URMC-099 to attendees from multiple medical and scientific institutions in Philadelphia.

Multi-Target Drugs Should Be in the Pharma Pipeline along with Precision Drugs

Thursday, January 31, 2019

“Precision medicine—providing the right treatment, for the right patient, at the right time—is saving lives. The use of therapies that home in on single targets is helping beat tough-to-treat diseases that were often deadly in the past,” writes Harris Gelbard, a professor of neurology, pediatrics, neuroscience, and microbiology and immunology, who is also director of the Medical Center’s Center for Neurotherapeutics Discovery. “But we’re overlooking another class of extremely important and promising candidates: multi-target drugs.”

Read More: Multi-Target Drugs Should Be in the Pharma Pipeline along with Precision Drugs