Koda-Kimble Seed Award recipients explore 'blue-sky' projects
Recipients of the UCSF School of Pharmacy 2017 Mary Anne Koda-Kimble Seed Award for Innovation will explore ideas ranging from possible new ways to treat obesity to new ways of accessing antibiotic-producing microbes found in soil. Five projects are being funded in this, the third round of awards since the fund was established in 2012.
Faculty, staff, and students from within the School; UCSF faculty members outside the School who teach the School's doctor of pharmacy (PharmD) students; UCSF PharmD residents; and postdoctoral scholars working with School faculty members were all encouraged to bring forward their boldest, riskiest, and most blue-sky ideas: proposals for which there is no ready or traditional source of funding. Project proposals could be large or small in scope.
Mary Anne Koda-Kimble, PharmD, served as the School’s dean from 1998 to 2012 and represented a leadership style of relentless support for new directions in science, education, and patient care. The Seed Award for Innovation honors her legacy.
No single discovery or solitary action will determine our success. My role as dean is to plant seeds that have the potential to take root and flourish. These could be novel research ideas, new methods of teaching or presenting our curricula, totally new approaches to delivering pharmaceutical care to patients and populations—even new ways of working with new partners. Innovation is key to our success; it must be constantly encouraged and nourished.
— Mary Anne Koda-Kimble, PharmD
The following projects chosen to receive 2017 Seed Awards will share more than $77,000 in total funding.
Cultivation-free discovery of antibiotic-producing soil microbes with droplet microfluidic single-cell screening
Principal awardees: Leqian Liu, PhD, postdoctoral researcher, Department of Bioengineering and Therapeutic Sciences; Adam Abate, PhD, faculty member, Department of Bioengineering and Therapeutic Sciences
Award funding: $9,500
The challenge: The spread of resistant bacteria—leading to untreatable infections—is a major public health threat, but the pace of antibiotic discovery to combat these pathogens has slowed. Nearly all antibiotics in use today are compounds that were discovered during the 1940s to 1960s. Most of these compounds were discovered by screening soil-derived actinomycetes against a susceptible test microorganism. The major limitation of this method is that it requires cultivation of the microbes. This requirement will inevitably exclude 99% of microbial species, since they are “uncultured.” This microbial dark matter represents the most promising untapped source of chemicals, and screening it for antimicrobial activity is an attractive path for novel antibiotic discovery. However, the lack of a cultivation method for these microbes makes them inaccessible for current antibiotic screening assays.
The project: To overcome this major limitation, we propose to develop a novel droplet microfluidic single-cell screening platform, allowing for cultivation-free antibiotic-producing microbe discovery, by screening antimicrobial activity of these “uncultured” microbes for the first time. In this proposed workflow, we will use a combination of advanced droplet microfluidic techniques that we specialized in the Abate Lab, including single-cell electrical lysis and encapsulation, droplet merging, and droplet sorting.
Predicting In Vivo Hepatic Clearance: Reevaluating the In Vitro–In Vivo Extrapolation (IVIVE) Assumptions
Principal awardees: Leslie Benet, PhD, faculty member, Department of Bioengineering and Therapeutic Sciences; Hideaki Okochi, PhD, assistant research scientist, Department of Bioengineering and Therapeutic Sciences; Jasleen Sodhi, PhD student, Pharmaceutical Sciences and Pharmacogenomics graduate program
Award funding: $10,000
The challenge: Drug development could be markedly accelerated with significant cost savings if sponsors could predict drug elimination kinetics prior to dosing in humans. A multitude of studies have attempted to utilize in vitro measures of drug clearance to predict in vivo drug clearance in humans (i.e., IVIVE: in vitro–in vivo extrapolation). But presently employed methodologies using human liver tissue in general markedly under-predict in vivo metabolic clearance, but not uniformly from drug to drug. And researchers in the field do not know why.
The project: Surprisingly, the theoretical basis of the methodology universally employed for these predictions has not been evaluated. Examination of the theoretical basis for IVIVE predictions reveal that the liver was assumed to function as a homogeneous system, rather than a heterologous environment composed of both aqueous and lipid components into which drugs distribute differentially. We have derived a new theoretical relationship, which this project will explore.
Novel therapeutic strategy to manipulate neuroendocrine pathway to treat obesity
Principal awardees: Navneet Matharu, PhD, postdoctoral scholar, Department of Bioengineering and Therapeutic Sciences; Nadav Ahituv, PhD, faculty member, Department of Bioengineering and Therapeutic Sciences; Christian Vaisse, MD, PhD, Department of Medicine, Diabetes Center
Award funding: $45,000
The challenge: The obesity trend in United States has posed significant challenges, not just for socioeconomic sectors, but also for biomedical researchers to devise novel avenues to understand and treat the obesity pandemic. Obesity is the leading cause of worsening metabolic syndrome (associated with diabetes and cardiovascular disease risks) in a majority of the population across age groups. The molecular genetic analysis based on monogenic obesity patterns has identified handful of genes (around 20 genes) with the leptin-Melanocortin 4 receptor (Mc4r) pathway as the key determinant of metabolism; however, genome wide association studies (GWAS) identified around 100,000 SNPs associated with polygenic obesity trait, with FTO gene having the maximum known variants. Both of these approaches agree on common ground that: 1) physiological aspects of obesity are neuroendocrine in nature and the crosstalk between nuclei of the hypothalamus defines the course of development of the obesity phenotype; 2) variants of genes identified in monogenic obesity studies are also implicated in polygenic obesity traits.
The project: Considering the fact that many obese patients don’t respond to the conventional obesity drug therapy suggests that mutation-specific precise drug therapy for obese patients is still the unmet need. In the absence of a reliable hypothalamic cell culture system that could enhance drug identification, we have to rely on mouse models of obesity. There are several mouse models available for monogenic obesity where the expression of the functional copy of a mutant gene could rescue the obesity phenotype (as well as for polygenic obesity), which can provide animal models to test obesity therapies. Knowing that the neuroendocrine system in the hypothalamus is the master seat that controls the metabolism of the body, and abrogation in Mc4r and FTO pathway being the hallmark of both monogenic and polygenic obesity, respectively: How can we quickly yet comprehensively test for putative drug targets of these two pathways in the absence of available cell culture systems for drug screens? There are around 20-odd genes that can serve as targets for devising therapies. If we can directly manipulate the neuroendocrine pathway in the hypothalamus in live animals and observe it for diabesity phenotype development, we can find the potential drug target/s.
The investigation of Angiotensin Converting Enzyme Inhibitors (ACE-I) and Angiotensin II Receptor Blockers (ARB) for protection against Parkinson’s disease
Principal awardees: Gha-hyun Jeffrey Kim, PharmD, a PhD student in our PharmD/PhD combined degree program; Xiang Zhao, PhD, postdoctoral scholar, Department of Bioengineering and Therapeutic Sciences
Award funding: $1,237
The challenge: While Parkinson’s disease is one of the most common neurological disorders—affecting millions of people worldwide—current therapies are still limited to the temporary relief of symptoms. With advancing health care and increasing life expectancy, it is of great importance to find ways to protect against and cure this neurodegenerative disease. However, finding a novel drug to treat neurological disorders is very challenging, with an average of 14.2 years and $1.8 billion involved for a single drug to be brought to market. ACE-Inhibitors and ARBs are well known anti-hypertensives that are generally considered first line therapy per JNC-8 guidelines. These drugs work in the renin-angiotensin system (RAS), inhibiting the function of angiotensin II, which is involved in vasoconstriction. Although the RAS for blood pressure lowering is well studied, there is convincing evidence that this RAS system is also in the brain. The functional role of brain RAS is not well understood, but some hypothesize that the activation of angiotensin II disrupts cognition and generates reactive oxygen species (ROS). These ROS can damage the healthy dopamine neurons, which is the key feature of Parkinson’s disease. In addition, microglia will proliferate and release cytokines, which facilitate dopamine degeneration.
The project: Since ACE-I and ARBs work to inhibit angiotensin II activation, it might be possible to use these common drugs to slow disease progression and protect those patients who are at high risk for Parkinson’s. This project will investigate that possibility.
Constructing the Foundation for Big Data Analytics in Clinical Pharmacy Practice
Principal awardees: Scott Myers, MS, a PharmD student; Patricia Babbitt, PhD, faculty member, Department of Bioengineering and Therapeutics; Marcus Ferrone, PharmD, JD, faculty member, Department of Clinical Pharmacy; Rebecca Miller, MS, director, Office of Education and Instructional Support; Rodney Yun, education systems analyst, Office of Education and Instructional Support
Award funding: $11,362
The challenge: The future of the field of pharmacy will require a stronger emphasis on technology integration to maintain a competitive edge and to train the pharmacists of tomorrow. Student comfort in using current and future technologies relies heavily on today’s opportunities to engage and experience with what these new tools can bring to research and clinical practice. Health care professionals, and the education system that trains them, are on the precipice of a modernization wave that integrates in big data analytics. Incorporation of data sciences is often cited as the largest revolution coming to all of healthcare. This growing importance has recently begun to be addressed in some medical school curriculum revisions. Data application is more pertinent than ever in pharmacy and pharmaceutical sciences. Understanding data analytics is vital right now, and will continue to grow in importance for several aspects of pharmacy practice. These include: applications of pharmacotherapy quality improvements, health economic outcomes studies, business-side decision making, and more accurate modeling for precision medicine. Current students will have to grasp these concepts in the near future—either as analytical contributors or as clinicians—to translate results into practice. Despite the growth of big data in healthcare practice, current PharmD training in the field remains, at worst, entirely absent; at best, it employs lackluster training that utilizes technologies that are rapidly becoming obsolete.
The project: To overcome the problem, this proposal looks to prepare for the coming wave of modernization by immediately furnishing the necessary tools and by training students to utilize current and new technology. This will promote student investigations into the ever-increasing availability of clinical data; reinforce core didactic curriculum; create a new facet of critical thinking; strengthen statistical knowledge; and, finally, integrate and expand Inquiry Immersion project opportunities in the new curriculum.
About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school west of the Mississippi River. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.