UC San Francisco received more than $575.6 million in federal funding from the National Institutes of Health in 2016. The highly competitive awards and grants are crucial to advancing the research across our schools of dentistry, medicine, nursing, pharmacy and the Graduate Division.
The funding supports research and education across multiple health-science arenas at UCSF. It also advances scientific health research that helps us better understand key biological functions and translate findings into treatments and cures for patients.
Below are a few highlights of researchers who received the most NIH funding and how their NIH grants are helping them to change the future of health.
1. Diane Havlir, $12,395,178
2. Dean Sheppard, $6,281,170
3. Alexander Marson, $6,142,102
4. John Fahy, $6,085,587
5. Steven Deeks, $5,656,950
It has long been known that genetics control the immune system, but how remains a question. Alexander Marson, MD, PhD, assistant professor of microbiology and immunology, has spent the last 10 years answering that question by exploring the genetic circuits that control specific aspects of immune cell function to understand how variations in genetics contribute to different diseases.
Marson’s goal is to use that understanding to point toward new therapies – both by finding new targets for drugs and by actually changing the genetics of immune cells to give them new functions to treat cancer, autoimmune diseases and infections affecting the immune system, such as HIV.
Marson’s studies rely on CRISPR technology, which enables researchers to cut out and replace, or “edit,” genetic sequences within living cells to understand and treat disease.
“CRISPR provides the scalpel to go in and cut out some part of the human genome and potentially even replace part of it,” Marson said. “That is just an incredible ability, to truly understand how the genome works.”
One of Marson’s current projects – with collaborators in the UCSF Diabetes Center and Institute for Human Genetics – is focused on the genetics of type 1 diabetes, but is applicable to multiple common autoimmune diseases. Marson’s team will use cutting-edge CRISPR genome engineering to understand the precise ways that genetic variation affects the development of type 1 diabetes.
A second study is focused on HIV, but also relies on genome engineering – in this case, to uncover how genetics control the interaction between human T cells and the virus. Marson and colleagues have already developed an unprecedented technique to manipulate genome sequences in human T cells and render them resistant to HIV infection. An NIH grant will allow him to use this technology to search for new drug targets aimed at infected cells where currently available medicines are not effective, an effort that could eventually contribute to a cure.
“I had an HIV clinic for years,” he said. “I am strongly motivated by patients to figure out how we can cure the virus.”
1. Ruth Greenblatt, $4,115,106
2. Kathleen Giacomini, $2,040,471
3. Esteban Burchard, $2,025,601
4. Shuvo Roy, $1,566,286
5. Michael Fischbach, $1,466,125
Membrane transporters are proteins that determine how many small molecules pass through biological membranes. As the gatekeepers to our cells, they play an important role in how drugs are absorbed, distributed and eliminated by our bodies and whether therapies achieve their intended effect.
Kathleen Giacomini, PhD, professor of bioengineering and therapeutic sciences, studies how genetic differences, in particular those that affect membrane transporters, may explain why a drug works in some people but not in others. Her research is helping to overturn the one-size-fits-all approach to treating common conditions, and it may help physicians predict which patients will need higher doses or alternative drugs.
One recent study looked at the standard first-line treatment for type 2 diabetes, the drug metformin, which works well in about two-thirds of patients but not in the rest. To understand how genetic variations may underlie such variable metformin response, Giacomini co-led a genome-wide association study of more than 10,000 patients of different ethnic backgrounds with her collaborator Ewan Pearson, PhD, professor of diabetic medicine at the University of Dundee in Scotland. The study identified genetic variations in the SLC2A2 gene that encodes for a glucose transporter, which were associated with greater response to metformin.
“Instead of treating everyone with type 2 diabetes the same way, we may be able to use specific genetic markers to provide a more tailored approach to their medications,” said Giacomini.
Another study looked at allopurinol, a common treatment for chronic gout, that also has highly variable results in patients for unknown reasons. Similarly, Giacomini’s team was able to identify a membrane transporter gene, ABCG2, that was associated with better response to allopurinol.
Such discoveries from Giacomini’s lab highlight the importance of having large, diverse study populations and bring us closer to a precision medicine approach to treating diabetes and other conditions.
1. Jon Levine, $1,717,805
2. Ophir Klein, $1,436,875
3. Carol Gross, $1,016,139
4. Sarah Knox, $1,030,201
5. Shingo Kajimura, $941,363
Humans have two types of fat cells that function in remarkably opposite ways: white fat stores energy and is linked with diabetes and obesity, while brown fat burns energy and is associated with leanness.
For several years, Shingo Kajimura, PhD, has been studying how white fat can be converted into a temporary form of brown fat, known as beige fat. The identify switch can occur in response to external cues such as chronic cold exposure, exercise, burn injury and bariatric surgery.
“We’re trying to understand how energy storing white fat can be converted into heat-generating brown fat,” said Kajimura, associate professor of cell and tissue biology. “By engineering fat cell fate we may be able to counteract obesity and diabetes.”
If thermogenic beige fat can be created and maintained, researchers hope to recruit its energy-burning capacity to help obese patients lose weight. “In mice, we’ve learned how to convert white fact into beige fat and now the challenge is understanding how to protect the beige fat from reverting back,” said Kajimura.
His lab is also working to understand the developmental biology of brown fat: how it’s made, where it comes from and how it’s regulated.
More recently, Kajimura’s lab has found that brown fat seems to have anti-diabetic effects that are separate from its anti-obesity effects. In animal models, they are investigating the mechanisms by which increased brown fat improves glucose homeostasis, which could provide a foundation for new treatments for type 2 diabetes.
They have found that brown fat communicates with other organs, like the liver, to regulate how much heat is dissipated. “We have data telling us that brown fat secretes molecules that allow it to talk to other organs,” said Kajimura.
1. Sandra Weiss, $1,190,127
2. Christine Miaskowski, $1,117,002
3. Janet Shim, $575,764
4. Xiao Hu, $540,309
5. Julene Johnson, $530,276
Exposure of a fetus to stress-related hormones may affect development of brain areas that shape an infant’s response to stress after birth, and an infant’s ability to cope with stress can have lasting consequences for later mental and physical health.
Sandra Weiss, PhD, RN, is studying how corticosteroids commonly given to women at risk of preterm delivery and a mother’s own stress hormones may program development of the stress-response system in preterm babies.
Corticosteroids help promote fetal lung development and reduce the risk of death. But Weiss’s team hypothesizes that fetal exposure to corticosteroids and the mother’s heightened stress hormones may modify development of the infant’s stress response system, known as the HPA axis.
“Our initial data suggests that babies whose mothers receive corticosteroids have difficulty mounting a normal response to stressors, as shown in suppressed cortisol levels and dampened heart rate variability. This difficulty wasn’t found among babies whose mothers didn’t receive corticosteroids,” said Weiss, interim dean and the Robert and Delphine Eschbach Endowed Chair in Mental Health.
Weiss is following infants through their first year of life to assess how hormonal exposure in the womb will affect a number of their physiologic responses and emotional regulation. Her team is also studying effects on the infant’s telomeres, protective caps on the ends of chromosomes, as an indicator of cellular integrity.
Another major focus of Weiss’ lab is how maternal depression may compound any adverse effect of corticosteroids. Mothers of preterm babies are more likely to experience postpartum depression, which can influence how they respond to a baby’s distress. “It can be very difficult for women who are struggling with their own emotional challenges to help reduce their infant’s distress in optimal ways,” said Weiss.
“Our results will hopefully help clinicians weigh the risks and benefits of corticosteroids, identifying who may be at greatest risk from any adverse effects. We can then tailor interventions for those who are most vulnerable in light of their stress and depression profiles,” said Weiss.
1. Clinical and Translational Sciences Institute (PI: Jennifer Grandis), $19,828,278
2. Helen Diller Family Comprehensive Cancer Center (PI: Alan Ashworth), $8,782,539
3. Autoimmunity Center of Excellence (PI: David Wofsy), $6,137,707
4. HARC Center: HIV Accessory and Regulatory Complexes (PI: Alan Frankel), $3,929,597
5. UCSF-GVI Center for AIDS Research (PI: Paul Volberding), $2,952,540
Autoimmune diseases are the result of the immune system mistakenly attacking the healthy tissues of the body. David Wofsy, MD, has spent his whole career exploring how autoimmune diseases occur, and he is using that insight to develop biologic approaches to treat people suffering from these conditions.
Over the course of Wofsy’s career, the field has shifted from immunosuppressive therapy that affects the entire immune system to developing much more selective treatments by targeting specific parts of the immune system.
Progress in establishing a sound scientific understanding of the causes of these diseases has resulted in therapies that have had a significant impact on a few autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and irritable bowel disease, he says.
But it leaves very many where the same progress has not yet been made.
Wofsy heads the Autoimmunity Center of Excellence Clinical Research Program at UCSF, which is examining the potential for using the patient’s own regulatory T cells to treat systemic lupus erythematosus, a disease in which the immune system attacks a wide range of tissues, including the kidneys, lung and brain. Another project underway will examine the therapy in pemphigus vulgaris, a rare autoimmune disease that causes painful blistering on the mucous membranes, which can include the mouth, eyes, genitals or lungs.
The broad goal of the Russell/Engleman Rheumatology Research Center at UCSF, which Wofsy directs, is to translate advances in immunology and molecular biology into practical, safe and effective therapies for people with autoimmune diseases.
“What excites me the most is that as we understand mechanisms in the body that protect us against immunological diseases, we can harness them to treat or correct immunological abnormalities,” he said. The aim is restoring balance to the immune system rather than broadly suppressing it entirely.
“Using existing mechanisms rather than toxic drugs is what I think the future holds,” he said. “And it is already beginning to happen.”