Research

Research Interests of Faculty​​ ​

Bruce A. Barshop, MD, PhD is an accomplished biochemical geneticist with expertise in metabolic disorders, and he is nationally recognized for his work on lysosomal storage disease, metabolomic testing, and cystinosis. His work in metabolic disease has led him to be a key intramural UCSD collaborator on numerous grants, or the San Diego site PI on multiple clinical trials, including trials for Fabry disease, Pompe disease, Gaucher disease, and urea cycle disorders. Dr. Barshop has focused on developing a state-of-the-art metabolomics research program, allowing colleagues at UCSD and elsewhere to leverage their own research projects. In conjunction with partner labs in Lipidomics (Dr. Dennis) and Glycomics (Dr. Esko), we constitute a large comprehensive metabolomics resource. Dr. Barshop has also continued to play a leadership role in the field of cystinosis, running a proteomics research study, advancing methods for intracellular cystine measurement, and supporting clinical trials.

Craig L. Bennett, PhD is interested in inherited motor neuron diseases, and has been focused upon ALS4, a juvenile-onset form of ALS caused by mutations in the senataxin gene. He is in the process of generating mouse models and iPSC models of this disease.

Lynne M. Bird, MD is the principal investigator on a large record review study through Sharp Memorial Hospital/Mary Birch Hospital for Women, designed to explore the association between growth patterns and types of congenital abnormalities seen in infants of diabetic mothers, to be analyzed in conjunction with the Epidemiology Program at San Diego State University. Dr. Bird is also the local site investigator in a collaborative endeavor to study Angelman syndrome (AS), as part of a large NIH-funded Rare Disease Clinical Research Network (RDCRN) to study AS, Rett syndrome and Prader-Willi Syndrome (PWS). She supervises two studies as part of this project, a natural history study, and a clinical trial to treat young AS patients with vitamin supplements and was also awarded two grants by the Angelman Syndrome Foundation to conduct AS studies, including a phase II trial of Levodopa. Dr. Bird also received funding from the Department of Pediatrics to establish a multidisciplinary clinic for the health supervision of children with PWS. The clinic has been operational for three years and is the only clinic in Southern California for the comprehensive evaluation and management of individuals with PWS; one goal of the clinic is to facilitate participation in clinical research on PWS, in collaboration with University of California Irvine where patients can be enrolled in the RDCRN natural history study.

Stephanie Cherqui, PhD.  Dr. Cherqui's laboratory focuses on developing stem cell and gene therapy strategies for degenerative multi-systemic disorders such as cystinosis, and to understand the molecular mechanisms by which hematopoietic stem cells can lead to tissue repair in non-hematopoietic genetic diseases. Using a mouse model for cystinosis, she showed that syngeneic hematopoietic stem and progenitor cell (HSPC) transplantation from wild-type donors into Ctns-/- mice led to significant decreases of cystine in every tissue tested and the impact correlated with the abundant tissue integration of bone marrow-derived cells. This treatment also protected these animals from the progression of the kidney tissue injury if a relatively high level of donor-derived blood cell engraftment of Ctns-expressing cells was achieved. This work represents the first proof of concept for using HSPC transplantation as a therapy for cystinosis and led to the first stem cell clinical trial for this disease. Because of the risks associated with allogeneic stem cell transplantation, the long-term goal is to develop autologous HSPC transplantation using a lentivirus vector to introduce a functional version of CTNS. A pre-IND has been submitted and reviewed by the FDA in April 2013. The pharmacology/toxicology studies to test the safety of the lentiviral vector construct have now started and should lead to an IND for a phase I clinical trial for cystinosis.

Theodore Friedmann, MD, PhD continues to study Lesch Nyhan Disease (LND), a metabolic disease characterized by profound neurodevelopmental abnormalities. His lab is concentrating on microarray and proteomic characterizations of human fibroblasts derived from LND patients, and of affected brain regions of the HPRT gene knockout mouse model. Dr. Friedmann’s lab has identified a number of genes and gene families that are aberrantly expressed in LND, and is presently examining their potential role in the development of the disorder’s neuropathology. The lab is using microarray and proteomic approaches to characterize the molecular basis for the defect in basal ganglia dopamine pathways by characterizing the molecular events that accompany the differentiation of human embryonic stem cells toward the dopaminergic neuronal phenotype. Dr. Friedmann is continuing to study the assembly and gene transfer properties of synthetic virus-like nanoparticles (virosomes), and the molecular mechanisms of growth enhancement by the growth factor IGF-1 in cultured cells and in mice in vivo. In addition, he has continued an extensive series of studies in vitro and in vivo of the mechanism of action of insulin-like growth factor (IGF-1), using gene expression and proteomic approaches. As part of that research program, he has established a bioinformatic facility under the sponsorship of the World Anti-Doping Agency (WADA) that will coordinate the worldwide research program of growth factors and related functions under the auspices of WADA.

Marilyn C. Jones, MD conducts research into the clinical delineation of birth defect patterns, the natural history of syndromes, genotype/phenotype correlations, the elucidation of normal and abnormal mechanisms of morphogenesis, and the impact of prenatal diagnosis on clinical management.

Albert R. La Spada, MD, PhD applies the tools of molecular genetics, neuroscience, and functional genomics to understand mechanisms of neurological disease. His research program is focused upon human genetic diseases caused by expansions of trinucleotide repeats, including Huntington’s disease, spinobulbar muscular atrophy, and spinocerebellar ataxia type 7. He has found that transcription dysregulation and activation of apoptosis / autophagy are important in neurological disease. His lab has learned that protease function and proteolytic cleavage regulate key events in pathogenesis. His lab’s goal is to define molecular and cellular pathways by which neurons become dysfunctional and use this knowledge to devise rational therapies. Focus areas include: failure of protein quality control underlies all major neurological disease: Identification of genetic pathways that regulate autophagy and the role of mTOR signaling in neuroprotection; altered gene transcription in neurological disease and retinal degeneration; unraveling the complexity of CNS gene regulation, including microRNAs and non-coding RNAs; bioenergetics of neurons, and understanding mitochondria dysfunction in neurological disease, including mitophagy and mitochondrial dynamics; and cross-talk between the insulin signaling pathway and neurological disease pathways. Dr. La Spada’s group also is involved in translational research, and is currently advancing therapies for spinobulbar muscular atrophy, Huntington’s disease, and spinocerebellar ataxia type 7 in mouse and human stem cell models of these inherited disorders.

Fred Levine, MD, PhD is continuing his research on the relationship between growth and differentiation of the human endocrine pancreas. The ultimate goal of this work is to develop a sufficient understanding of beta-cell regeneration to allow for the development of a beta-cell replacement therapy for diabetes. To this end, Dr. Levine’s lab has developed cell lines from the endocrine cells and endocrine precursor cells of the human adult and fetal pancreas. The cell lines express low levels of islet hormones, and are being used as platforms for high-throughput screening, as well as for fundamental studies of beta-cell growth and differentiation. The laboratory is also studying primary adult human non-endocrine pancreatic epithelial cells. Having shown that they can function as endocrine progenitors, they are pursuing mechanistic studies to determine the molecular basis for beta-cell differentiation from those cells.

Alysson Muotri, PhD is interested in the mechanistic basis of neurodevelopmental disease, including Rett Syndrome. His laboratory uses animal models, neural stem cells, human pluripotent cells and various other molecular tools to investigate fundamental mechanisms of brain development and mental disorders. He is particularly well known for his expertise in the application of induced pluripotent stem cell (IPSc) technology to the study of neurodevelopmental disease. Dr. Muotri’s laboratory also explores mobile elements, such as retrotransposons, as generators of diversity during neuronal differentiation. These mobile elements may be part of a conserved core process responsible for evoking facilitated complex non-random phenotype variation through which selection may act.

Robert K. Naviaux, MD, PhD is conducting research in autism and mitochondrial medicine. His team at the UCSD Mitochondrial and Metabolic Disease Center identified the first causative mutations in a gene called POLG (the mitochondrial DNA polymerase γ) as the cause of Alpers syndrome. Since this discovery, dozens of new mutations have been found, and DNA testing has now become the gold standard for confirming the diagnosis of Alpers syndrome around the world. In addition, the Naviaux lab collaborates with labs across the country on projects ranging from the development of non-invasive methods for mitochondrial disease diagnosis to the role of mitochondria in embryogenesis, stem cell differentiation, cancer, diabetes, and tissue regeneration.

William L. Nyhan, MD, PhD has had a long series of clinical studies and therapeutic trials, most notably including studies of Lesch-Nyhan disease. He has several long-standing protocols for systematic evaluation of purine metabolism, amino acid metabolism, and fatty acid oxidation. He is the PI of a project to investigate the efficacy of tetrahydrobiopterin in correcting neurotransmitter abnormalities in Lesch-Nyhan disease. Another clinical trial of nitisinone in alkaptonuria has been approved. He has recently re-established a facility for mutational analysis for HPRT deficiency in the ​​laboratory.

Tariq Rana, PhD.  Dr. Rana's laboratory has discovered fundamental structural and functional features of small RNAs required for gene silencing in human cells. In addition, his laboratory has uncovered mechanisms involving small RNAs and RNA-protein complexes in regulating host-pathogen interactions. Dr. Rana received his Ph.D. from the University of California at Davis and he was an American Cancer Society fellow at the University of California at Berkeley. He is a recipient of numerous awards including a Research Career Award from the National Institutes of Health in 1996. Dr. Rana has advised a number of biotechnology companies and has served as a member of several Scientific Advisory Boards. He was a Professor of Biochemistry and Molecular Pharmacology and founding Director of the Program in Chemical Biology at the University of Massachusetts Medical School, Worcester, Massachusetts, prior to joining the Sanford-Burnham Medical Research Institute in 2008. He held Sanford-Burnham Professorship and served as the founding director for the RNA Biology Program from 2008 to 2014. Currently, he is a Professor of Pediatrics and V/C for Innovation in Therapeutics at the University of California San Diego School of Medicine, where his laboratory studies RNA regulation of development and disease