Laura Bull, Ph.D.
Associate Professor of Medicine



Contact Information:
Phone: (415) 206-4807
SFGH, Bldg. 40
lbull@medsfgh.ucsf.edu

Links:
Biomedical Sciences

Publications:
Selected Publications

The main focus of my laboratory is on increasing our understanding of the biology of the liver and enterohepatic circulation in health and disease, through the application of genetic approaches. Studies of several liver diseases are ongoing in my laboratory, and each project is at a different stage. These projects include the following:

1. Study of disease caused by mutation in FIC1(ATP8B1), and characterization of mouse models of ATP8B1 disease.
ATP8B1 is a P-Type ATPase present in many tissues, and likely to function as an aminophospholipid flippase. Several years ago, I led a project resulting in its identification as the protein defective in two forms of hereditary liver disease differing in their severity. My laboratory currently pursues several strands of research on ATP8B1, including the following:

a) Characterization of a mouse model of ATP8B1 disease. We have generated a mouse carrying a mutation in Atp8b1; this mutation is also seen in a number of human patients with ATP8B1 disease. In a collaborative study, we have performed extensive evaluation of the phenotype of this mouse, and additional such studies are planned. Our findings in this mouse model were unanticipated, as they indicate that, in the mouse model of ATP8B1 disease, the primary defect is in regulation of intestinal reabsorption of bile acids, rather than in transport of bile acids out of the liver. This finding suggests the novel hypothesis that excessive intestinal reabsorption of bile acids could contribute to development of liver disease in human patients. We have suggestive evidence that the phenotype of this mutant mouse may be more severe in a different strain from the one in which we have studied it to date, so we are performing a backcross to introduce the mutation into this second strain. If the mutant phenotypes in the two strains are distinct, we may pursue genetic mapping of modifier loci responsible for the inter-strain differences in phenotype.

b) Creation of a second Atp8b1 mutant mouse. We are currently generating a second mouse model of ATP8B1 disease, using a construct that will permit conditional knock-out of the murine gene. We anticipate generating mice with intestine- and/or liver-specific loss of Atp8b1 function. With these mutant strains, we should be able to further evaluate the role of regulation of intestinal bile acid reuptake in liver disease.

c) Phenotype-genotype correlation studies in hereditary cholestasis. We have performed large-scale mutation screening of patients with hereditary cholestasis, using DHPLC and DNA sequencing. We are participating in a collaborative study in which we are comparing clinical, biochemical, histopathological, and treatment-outcome data in patients with liver disease due to ATP8B1 mutation and in patients whose liver disease is associated with mutation in ABCB11 (which encodes the hepatic bile salt export protein). The goals of this study are to enable more accurate clinical diagnosis of hereditary cholestasis, and prediction of treatment outcomes, and to increase our understanding of the biology of these genetically distinct disorders.

2. Genetic studies of lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome).
In this disorder, patients typically suffer transient but severe liver disease early in life, and develop chronic lymphedema. Through study of Norwegian LCS patients using population genetic mapping techniques, we have mapped a locus for this disease to chromosome 15. We are performing high-resolution genetic mapping studies and evaluation of candidate genes to identify the mutated gene.

3. Genetic studies of Familial hypercholanemia (FHC).
We are performing genetic mapping studies of this disorder in Amish families. Using only a small set of patients, in combination with highly efficient mapping techniques, we have mapped two loci for FHC in the Amish. We have identified a putative disease mutation in a gene in one of these regions, and are evaluating a promising candidate gene in the second region. We also have evidence suggesting a 3rd FHC locus exists in the Amish. Our data indicate that FHC is a disorder that demonstrates unanticipated genetic complexity.

4. Evaluation of genetic factors influencing susceptibility to 'secondary' liver diseases, including drug-induced cholestasis.
It is likely that variants in some of the genes we and others have identified as being mutated in Mendelian liver disorders also affect susceptibility to more common, secondary forms of liver disease, such as intrahepatic cholestasis of pregnancy (ICP), steroid-induced cholestasis (including that induced by birth control pills), and cholestasis induced by surgery, sepsis, or non-steroidal drugs. We have begun collection of DNA from patients with ICP and steroid-induced cholestasis, as well as evaluation of candidate genes in these patients.

Selected publications:
Bull, L.N., Roche, E., Song, E.J., Pedersen, J., Knisely, A.S., van der Hagen, C.B., Eiklid, K., Aagenaes, O., Freimer, N.B. (2000) Mapping of the locus for Cholestasis-Lymphedema Syndrome (Aagenaes Syndrome) to a 6.6.cM interval on chromosome 15q. American Journal of Human Genetics, vol 67, pp. 994-999.

Morton, D.H., Salen, G., Batta, A.K., Shefer, S., Tint, G.S., Belchis, D., Puffenberger, E., Shneider, B., Bull, L.N., Knisely, A.S. (2000) Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol. Gastroenterology, vol 119, pp 188-195.

Bull, L.N., Juijn, J.A., Liao, M., van Eijk, M.J.T., Sinke, R.J., Stricker, N.L., DeYoung, J.A., Carlton, V.E.H., Baharloo, S., Klomp, L.W.J., Abukawa, D., Barton, D.E., Bass, N.M., Bourke, B., Drumm, B., Jankowska, I., Lovisetto, P., McQuaid, S., Pawlowska, J., Tazawa, Y., Villa, E., Tygstrup, N., Berger, R., Knisely, A.S., Houwen, R.H.J., Freimer, N.B. (1999) Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC. Human Genetics, vol 104, #3, pp 241-248.

Strautnieks, S.S., Bull, L.N., Knisely, A.S., Kocoshis, S.A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M.S., Kagalwalla, A.F., Németh, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N.B., Gardiner, R.M., Thompson, R.J. (1998). A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genetics, vol. 20, #3, pp.233-238.

Bull, L.N., van Eijk, M.J.T., Pawlikowska, L., DeYoung, J.A., Juijn, J.A., Liao, M., Klomp, L.W.J., Lomri, N., Berger, R., Scharschmidt, B.F., Knisely, A.K., Houwen, R.H.J., Freimer, N.B. (1998). A gene encoding a P-type ATPase is mutated in two forms of hereditary cholestasis. Nature Genetics, vol. 18, #3, pp. 219-224.