UCSF’s Top NIH-Funded Projects of 2018

By Nina Bai and Dana Smith

From understanding the basic building blocks of life to advancing the latest treatments for patients, more than a thousand projects across the University received federal funding from the National Institutes of Health in 2018, totaling more than $647.8 million.

The highly competitive grants and contracts that go to researchers in our schools of dentistry, medicine, nursing, pharmacy and the Graduate Division are crucial for supporting research across multiple health-science arenas at the University.

Below are some of the projects across the four professional schools that received the highest amounts of NIH funding in 2018.

Analyzing RNA Diversity Is Key to Understanding How Proteins Form

Stephen Floor (right), PhD, is leading a team that is studying how RNA result in distinct types and amounts of proteins. Photo by Susan Merrell

Stress granules are structures in the cell where RNA molecules that are not being translated into proteins are stored. The granules form through phase separation like oil and water. Image by Srivats Venkataramanan and Katie Blackwell 

High school biology textbooks need an update. New technology is revealing that the basic equation that one gene codes for one protein doesn’t hold up very well. It turns out that when DNA is copied into RNA, many variations of RNA can be produced, which results in different amounts or even types of proteins being made.

“Historically, we’ve measured short pieces of RNA, but that makes it really hard to figure out all the different kinds of RNA that a gene can make. So instead of trying to figure out what the different RNAs are doing, people have often assumed they all do the same thing,” said Stephen Floor, PhD, an assistant professor of cell and tissue biology in the School of Dentistry. “Now we have the tools to measure RNA in new ways, which enables us to understand how the RNA vary, why it matters, and how it changes between normal and diseased cells.”

Floor’s laboratory is using an innovative technique called long read sequencing that analyzes an entire strand of RNA instead of breaking it up into small chunks. The technology allows his team to study how the RNA behave and how they result in distinct types and amounts of proteins. He is particularly interested in changes to the regulatory stretches of RNA that give instructions about how much of a protein the cell should make.

One example of how biology uses these RNA variations is during development to dictate what type of adult cell a stem cell should turn into. A stem cell maturing into a neuron starts to produce RNA with longer regulatory sequences, which provide instructions about how the protein should be made. By the end of the process, the neuron's RNA can be up to 20 times longer than the stem cell's RNA, but they still come from the same gene and produce the same protein.

Floor said, “This is a hidden layer of regulation that we can now expose.”

To Reach More People, Tests for Dementia Are Moving Online

Michael Weiner (far right), MD, professor of Radiology, works with his team at the San Francisco VA Medical Center to develop online methods to predict and monitor cognitive decline. Photo by Susan Merrell

Even with billions of dollars invested in developing treatments for Alzheimer’s and other dementias, a major obstacle remains in finding people to join clinical trials. That’s because it can be very difficult to identify those who are at risk for or in the early stages of cognitive decline.

To make screening tools accessible to many more people, a team at UC San Francisco, led by Michael Weiner, MD, professor of radiology in the School of Medicine, is bringing them online. They are translating two widely used in-clinic tests for cognitive decline to electronic versions that can be taken at home.

The Clinical Dementia Rating (CDR) is an effective but labor-intensive screening tool that requires a clinician to interview not only the participant, but also a “study partner” – a close friend of family member – who can describe changes in the subject’s behavior.

“The powerful thing about the CDR approach is you can rely heavily on the study partner, who may be able to help us identify people who are at risk,” said Rachel Nosheny, PhD, assistant professor of psychiatry, who is developing the online CDR.

The challenge is translating open-ended interview questions into a streamlined, multiple-choice test that can be graded automatically, said Nosheny. She is working with John Morris, MD, a neurologist at Washington University in St. Louis who originated the CDR in the 1990s, other physicians and statisticians.

The other screening tool is known as the Financial Capacity Instrument (FCI), and measures a person’s thinking through basic financial tasks: how many quarters are in $6.75, or where to sign on a check, for example. Scott Mackin, PhD, associate professor of psychiatry, is leading the effort to create an online FCI. He is collaborating with Daniel Marson, JD, PhD, creator of the FCI, and Erik Roberson, MD, PhD, both at the University of Alabama at Birmingham.

After developing the online tests, the researchers hope to validate them with a four-year-long study of 520 participants, who will take both the in-clinic and online versions of the tests.

“The major goal is to demonstrate that the online versions will be comparable to the clinical versions in terms of diagnostic performance,” said Weiner.

The online tests will aid not only dementia research efforts, said Weiner, but will be essential once treatments become reality. “Someday we’re going to have effective treatments,” he said. “How are we going to determine who is in need of those treatments?”

Tinnitus and Hearing Loss in Cancer Survivors After Chemotherapy

Grace Mausisa (left), RN, a research nurse, conducts a hearing evaluation on Karen Newcomb, who is a study participant in a clinical trial that assesses hearing damage from chemotherapy. Photo by Susan Merrell

A large study of cancer survivors revealed that two types of front-line chemotherapy drugs – platinum compounds and taxane compounds – can cause hearing loss and tinnitus. Now, a follow-up project is trying to understand which patients are at risk, how the side effects impact patients’ quality of life and if there is any way to treat the impairments.

An initial study in 600 breast, gastrointestinal, gynecological and lung cancer survivors – the most common kinds of cancer – set out to assess another chemotherapy-induced side effect: peripheral neuropathy. The discovery of hearing loss and tinnitus in these patients was somewhat serendipitous, said Christine Miaskowski, RN, PhD, FAAN.

“We were quite surprised that about 40 percent of all patients who got these neurotoxic drugs reported hearing loss and/or tinnitus,” said Miaskowski, a professor in the School of Nursing. “There are reports of hearing loss in children and people treated for head and neck cancer, but there are virtually no reports of this type of toxicity in the other cancers. It’s not on oncologists’ radar to ask patients about hearing impairment, so the problem has gone undetected.”

Miaskowski’s team plans to bring the 600 patients back to do a detailed characterization of the types of hearing impairment they experience, how they relate to other neurotoxic side effects, and if they affect mood or cognitive function. Hearing loss has been linked to higher rates of depression and dementia in elderly people. Fortunately, the hearing damage appears to be treatable with hearing aids, which would go a long way toward improving survivors’ quality of life.

The scientists are also working to discover how the chemotherapy drugs cause the neurotoxic effects. They think that changes in gene expression and gene interactions damage the auditory nerve cells. By identifying the pathways that are most vulnerable to the drugs, researchers and clinicians could potentially intervene to prevent the neurotoxicity or better tailor cancer treatments to minimize the risk of side effects.

‘DNA Barcodes’ Speed the Decryption of Gene Regulation

Nadav Ahituv (right), PhD, works in the laboratory with assistant researcher Fumitaka Inoue, PhD. Photo by Susan Merrell

Cells in a tissue culture flask are grown in an incubator set to the temperature of the human body to study gene regulatory elements and their relationship to human diversity and disease. Photo by Susan Merrell

Only 2 percent of the human genome are protein-coding genes, which means that much of our DNA serves instead to regulate the expression of genes – like a massive switchboard controlling a few light bulbs.

Through the collective work of the Encyclopedia of DNA Elements (ENCODE) Consortium, many of these regulatory sequences have been identified, but which genes they control, how they control them, and how mutations in these regulatory elements affect health is still not well understood.

“We can easily find a gene in a genome now because we know the coding sequence and we know the language,” said Nadav Ahituv, PhD, professor in the Department of Bioengineering and Therapeutic Sciences in the School of Pharmacy. “But for regulatory elements, we still don’t know the language, so it’s hard for us to find them.”

To decode the hidden language of regulatory elements, Ahituv’s team have been developing technology to study them more efficiently and on a massive scale. They are aiming to characterize over 100,000 regulatory elements and use CRISPR/Cas9 genome editing to study the effect of alterations in some of these elements.

Ahituv’s team, in collaboration with the laboratory of Jay Shendure, PhD, at the University of Washington, have spent years developing massively parallel reporter assays (MPRA) that can test thousands of elements in one experiment. An initial innovation was to use a “barcode” system. Unlike commonly used fluorescent tags, limited to a few colors, the barcode system provides the ability to have “thousands of colors” and can precisely identify each sequence among thousands.

Another innovation, led by Fumitaka Inoue, PhD, an assistant researcher in the Ahituv lab, is a new lentivirus-based MPRA, which allows researchers to study DNA elements in a genomic context. While previous MPRAs used plasmids, which exist outside genomes, Inoue developed a lentivirus-based approach that integrates the barcode system into the genome, revealing a more complete and accurate picture of a DNA element’s function.

The new MPRA can currently test over 170,000 DNA elements in a single experiment, said Inoue. Moreover, with the addition of CRISPR genome editing, researchers can observe how mutations in an element change its function, like flipping a switch to see what it does. The team is initially focusing on liver cells but, armed with their new technology, plans to expand into many other cell types.