Success Stories - Fall 2017

Diane L. Barber, PhD
School of Dentistry - Cell & Tissue Biology
Pilot for Established Investigators in Basic and Clinical/Translational Sciences
New Direction to Identify Regulators of Lysosome pH Dynamics

Impaired proteolysis due to dysregulated lysosome pH is a hallmark of many diseases, including neurodegenerative disorders and cancer. The RAP funding we received will support a pilot project on lysosome pH (pHlys) dynamics that will be a new direction for our group and open new directions for investigating lysosome biology relevant to basic sciences as well as neurodegenerative diseases and cancer. The low pHlys of ~ 5.0 is necessary for optimal activity of lumenal acid-activated hydrolases and hence for lysosome functions in metabolic adaptation and quality control of proteins. The pHlys is higher in neurodegenerative disorders and diabetic nephropathy, which is predicted to decrease protein degradation and promote protein aggregation. In contrast, pHlys is predicted but not adequately validated to be lower in cancer cells, which may increase biomass production needed for increased proliferation. Our restricted knowledge of pHlys dynamics and its importance in normal cell functions and diseases is primarily because of two limitations – first is the lack of lysosome-specific pH sensors and second is an incomplete understanding of how pHlys dynamics is regulated. We recently resolved the first limitation by developing a novel pHlys biosensor, pHLARE, which we will use to resolve the second limitation by using a screening strategy with pHLARE to identify lysosome membrane proteins regulating pHlys. The regulators of pHlys we identify could be therapeutic targets to limit dysregulated pHlys in diseases, for example to lower the increased lysosomal pH with neurodegenerative disorders and hence maintain activities of acid-activated proteases for protein degradation.

Som Chatterjee, PhD
School of Medicine - Medicine
Pilot for Junior Investigators in Basic and Clinical/Translational Sciences
Novel signaling mechanism that controls beta-lactam resistance in Staphylococcus aureus

The RAP funding will allow me generate necessary preliminary data to set directions for an R21 proposal and will assist me towards a path of independence.

Madeline Deutsch, MD, MPH
School of Medicine - Family and Community Medicine
Pilot for Established Investigators in Basic and Clinical/Translational Sciences
Collecting gender identity and sexual orientation at the point of care by self-report: Implications in a diverse patient population

Sexual and gender minority populations experience health disparities that are driven in part by a lack of consistent collection of sexual orientation and gender identity (SOGI) data in healthcare contexts. Failing to collect these data impairs our understanding of the size and health characteristics of these populations. Additionally, direct patient care impacts of a lack of clear collection and use of these include failure to use chosen names or pronouns, incorrect assumptions made about family structures, sexual behaviors and risk, or reproductive health needs. I have led a recently completed 4 year process to include SOGI measures in the UCSF ApEX electronic health record (EHR), but our work has really only just begun; data are lacking on best practices for collecting this information from patients of all genders and sexualities in a diverse clinical setting. This RAP award will allow me to both develop a community advisory process and to enroll more than 200 participants recruited from waiting rooms at two UCSF primary care clinics to administer both SOGI questionnaires as well as an evaluation questionnaire to study appropriateness and effectiveness of these questions. My intention is to use the preliminary data obtained in this study to support a more broad NIH R01 proposal studying both patient and provider/staff factors in the collection and use of these data.

Alessandro Didonna, PhD
School of Medicine - Neurology
Pilot for Junior Investigators in Basic and Clinical/Translational Sciences
Cell-specific microRNA profiling in experimental autoimmune encephalomyelitis

The RAP Pilot Award for Junior Investigators in Basic and Clinical/Translational Sciences will help me to provide the most accurate description of microRNA (miRNA) contribution to the physiopathology of oligodendrocytes (OLs) upon autoimmune demyelination. OLs are the cells responsible for the formation and maintenance of myelin in the central nervous system (CNS) and represent a principal target of the autoimmune injury in multiple sclerosis (MS). The possible involvement of miRNAs in pathological demyelinating processes has been suggested by numerous studies. However, due to the extreme complexity of the cyto-architecture and cell heterogeneity of the CNS, the study of miRNA dynamics in specific cellular populations of the brain has been challenging. To overcome this limitation, I propose to use the novel cell-specific affinity-purification technique miRAP to isolate miRNAs from OLs after induction of experimental autoimmune encephalomyelitis (EAE), a murine disease model that recapitulates several features of MS. Next-generation sequencing will be used to characterize the OL-specific miRNA dynamics along disease progression. Clarifying the role of miRNAs in MS could represent a crucial strategy for the identification of still unveiled genetic and functional determinants of MS risk and for the discovery of novel therapeutic targets and biomarkers.

Annesa Flentje, PhD
School of Nursing – Community Health Systems
Mentored Scientist Award Program in HIV/AIDS
Epigenetic architecture of stress among sexual minority men living with HIV

This award from the Gladstone Institute of Virology & Immunology Center for AIDS Research will support us in examining the relationship between epigenetic mechanisms and minority stress among sexual minority (i.e., non-heterosexual) men living with HIV. Sexual minority individuals are at greater risk for mental and physical health problems. Minority stress, which includes experiences and expectations of discrimination, internalization of societal stigma, and concealment of sexual orientation, is the primary explanatory model for the greater rates of mental and physical health problems observed among sexual minority people. Our research is examining the biological mechanisms through which minority stress may impact the health of sexual minority people. This award expands our work examining the relationship between minority stress and gene expression to enable us to examine the relationship between epigenetic mechanisms (e.g., DNA methylation) and minority stress among sexual minority men living with HIV. The results will inform future work examining the social genomic determinants of health.

Jason Nagata, MD, MSc
School of Medicine - Pediatrics
Mentored Scientist Award Program in HIV/AIDS
Assessing the preliminary effects of a multisectoral agricultural intervention on the nutritional, sexual, and reproductive health of HIV-affected adolescent girls

HIV-related mortality among adolescents is on the rise and over half of incident HIV cases globally are among adolescents, particularly among girls. Food insecurity and poverty are important drivers of HIV vulnerability among adolescent girls, and contribute to worse nutritional, sexual and reproductive health (SRH) outcomes. While most approaches to improving adolescent nutritional and SRH outcomes have focused on individual-centered approaches alone, integrated family-level interventions that address the underlying context such as poverty and food insecurity may be more effective in reducing adverse nutritional and SRH outcomes. In mid-2016, a large cluster-randomized controlled trial called Shamba Maisha (SM) was launched to evaluate the impact of a household-level multisectoral agricultural and finance intervention in Nyanza Region, Kenya on the health outcomes of 704 adults (RO1 MH107330) and 352 young children (RO1 MH109506). Consistent with NIH, UNAIDS, and WHO’s research priorities for adolescent health, I propose to leverage the infrastructure provided by this cluster randomized controlled trial to recruit adolescent girls residing in Shamba Maisha households and assess the preliminary impact of Shamba Maisha on adolescents’ nutritional and SRH outcomes at study endline. The central hypothesis is that improvements in household FI and wealth will contribute to reduced malnutrition, sexually transmitted infections, HIV, and unintended pregnancies among adolescent girls.

David L. Pennington, PhD
School of Medicine - Psychiatry
Under-represented Faculty in Clinical and Translational Research Awards
Effects of Active Virtual Reality Working Memory Retraining on Heavy Drinking Veterans with Mild Traumatic Brain Injury

This Under-Represented Faculty RAP Award will allow us to broaden the scope of our research program to include the implementation and investigation of innovative technology based interventions designed to increase self-control over alcohol use and other high-risk behaviors. Heavy alcohol use results in over half of all alcohol-related deaths, contributes to high-risk behaviors such as violence and suicide, and is strongly linked to traumatic brain injury. Mild traumatic brain injury (mTBI) is the most common form of head injury, especially among service members, and is associated with increased risk for heavy alcohol use. Both working memory training and exercise can be used to enhance cognitive function and promote recovery from alcohol use disorder (AUD). A growing body of evidence supports the use of virtual reality (VR) technology as an innovative therapeutic tool with specific applications to promote neuroplasticity during recovery from mTBI and AUD. This RAP award will facilitate the investigation of a physically active VR working memory retraining (VR-WMR) regimen designed to enhance neuroplasticity and promote engagement in training among heavy drinking Veterans with mTBI. The synthesis of physical activity and an enriched VR environment is expected to yield greater motivation to engage and complete a working memory training regimen, thus fostering greater improvements in executive function than traditional programs.

Licia Selleri, MD, PhD
School of Dentistry – Orofacial Sciences
Team Science Grant
Genomic regulation of midfacial outgrowth variation in evolution and pathology

Craniofacial morphogenesis demands coordinated outgrowth of multiple facial prominences that are initially spatially separated. Underscoring this complex choreography, 1/3 of all human birth defects affect craniofacial development. Both orofacial clefting and malocclusions are common birth abnormalities that affect the midface. During development, regulatory genes control the dynamics of transcriptional activity, tissue-level patterning, and intercellular signaling to modulate the timing of morphogenetic processes. Our goal is to define regulatory landscapes underpinning midfacial outgrowth in different species (mouse, chick, and pig) in order to understand how morphogenesis of the craniofacial complex is coordinated with variation in the growth of specific skeletal elements. Changes in these dynamic processes and underlying regulatory mechanisms underpin both evolutionary divergence in midfacial outgrowth and the etiology of craniofacial birth defects. This award will allow us to generate preliminary results in collaboration with Dr. Ralph Marcucio as the foundation for a future RO1 grant application.

Shylaja Srinivasan, MD
School of Medicine – Pediatrics
Family Support Award
Understanding the determinants of metformin pharmacokinetics in children

The prevalence of type 2 diabetes is increasing in children, and studies have highlighted differences between youth-onset and adult-onset type 2 diabetes. Metformin is the only oral medication that is approved for use in children with type 2 diabetes and despite a similar dosing regimen, youth with diabetes treated with metformin have higher treatment failure rates when compared to adults with type 2 diabetes. The overall goal of my research is to use genetic approaches to improve preventative and therapeutic strategies for type 2 diabetes in children and the objective of my RAP proposal is to examine current dosing strategies for metformin in children with type 2 diabetes and to understand the sources of variability in the pharmacokinetics of metformin in children particularly with regard to age and body size. As a junior faculty member, RAP funding will provide valuable support as I collect preliminary data towards a K23 proposal.

Peter J. Turnbaugh, PhD
School of Medicine – Microbiology & Immunology
Shared Technology Awards
Accelerating gnotobiotic research with an advanced biocontainment housing system

The Gnotobiotic Core facility allows researchers to establish causal links between microbes and a wide range of research topics and diseases. Our core maintains germ-free lines of standard wild-type mouse strains, and rederives transgenic lines into the germ-free state. Mice can then be colonized with a defined bacterial species or community in order to study the influence of microbes on the host or disease state. Traditionally, the maintenance and experimental manipulation of gnotobiotic mice has been performed in large isolators, requiring a tremendous amount of space, time, and cost for each colonization group. This award will enable us to purchase a new, revolutionary type of animal housing system, whereby individually HEPA-filtered cages are used in lieu of experimental isolators. This new technology allows each 6 cubic foot isolator to be replaced by 1-2 traditionally-sized mouse cages, increasing the maximum number of concurrent experimental groups 3-fold over our current setup while substantially decreasing the footprint of each group. It will also decrease the amount of downtime between experiments, allowing for greater access to gnotobiotic technology for all users of our core. To use this new technology or learn about our core, please visit gnotobiotics.ucsf.edu