David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Fall Quarter 2006

Every 2nd and 4th Mondays, 11am - 12pm, Gonda Center Conference Room - Room 1357

Mon, Oct 16
“Model systems for understanding steroid hormone receptor roles in cancer: a functional genomics approach”
Christina Jamieson, PhD, Assistant Professor, UCLA, Department of Urology and Department of Human Genetics
Contact & Intro: Chiara Sabatti
Mon, Oct 23
“Breast cancer: obesity and genetics”
Catherine L. Carpenter, PhD, MPH, Assistant Professor of Medicine, Center of Human Nutrition, David Geffen School of Medicine at UCLA
Contact & Intro: Paivi Pajukanta
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ABSTRACT: Genetic polymorphisms, an important underlying cause of obesity, may function by interacting with overabundance of food and lack of exercise to promote a higher percentage of obesity among susceptible groups. Obesity and adulthood weight gain increase breast cancer risk after menopause. Data suggests there may be an interaction between obesity and susceptibility to breast cancer. Polymorphic variants that promote the occurrence of obesity may also increase breast cancer risk. Dr. Carpenter will address these issues by presenting results from case-control studies and clinical studies.

LITERATURE:
  1. Effect of family history, obesity and exercise on breast cancer risk among postmenopausal women. Carpenter CL, Ross RK, Paganini-Hill A, Bernstein L. International Journal of Cancer 106: 96–102 (2003).
  2. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. King MC, Marks JH, Mandell JB, for the The New York Breast Cancer Study Group. Science 302: 643-646 (2003).
  3. Genetic variation and cancer: improving the environment for publication of association studies. Rebbeck TR, Martinez ME, Sellers TA, Shields PG, Wild CP, Potter JD. Cancer Epidemiology, Biomarkers and Prevention 13: 1985-1986 (2004).
Mon, Nov 06
“Niemann-Pick Disease: from genetics to HDL structure and metabolism”
Michel Marcil, MSc, PhD, Assistant Professor, McGill Faculty of Medicine, Division of Cardiology Research, McGill University Health Centre, Royal Victoria Hospital
Contact & Intro: Paivi Pajukanta
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ABSTRACT: Studies in our laboratory have been investigating potential genes governing plasma high-density lipoprotein (HDL) levels, particularly in severe familial HDL deficiency. In addition to our studies on ABCA1, a critical component in HDL formation, we have investigated the molecular genetics and pathophysiology of HDL deficiency in Niemann-Pick disease (NPD) type B. We characterized a kindred with compound heterozygous mutations on the sphingomyelin phosphodiesterase-1 (SMPD1) gene, coding for the lysosomal (acid) and secretory enzyme sphingomyelinase (SMase). Functional gene defects in SMPD1 cause a deficient activity of the lysosomal SMase and the types A and B NPD, characterized by sphingomyelin accumulation in reticuloendothelial cells and other cell types throughout the body. Although it is documented that NPD type A and B patients have low levels of HDL cholesterol and increased risk of atherosclerotic heart disease, the link between acid SMase deficiency and low HDL cholesterol has not been determined. It has been suggested that the sphingomyelin molecules inhibited the unfolding of apoA-I in discoidal and spherical reconstituted HDL and impaired the lecithin:cholesterol acyl transferase (LCAT) reaction critical for HDL maturation. Recent studies from our group have led to a better understanding of the molecular basis of HDL deficiency in NPD type B patients with the identification of secretory sphingomyelinase (S-SMase) as a critical intravascular remodeling factor believed to play a specific role in the hydrolysis of HDL sphingomyelin; as the second most abundant phospholipid in lipoprotein, sphingomyelin is known to be a potent physiological inhibitor of LCAT. Thereby, S-SMase and LCAT might act in concert and together to mediate the maturation of nascent HDL particles and hence may constitute a molecular basis for HDL biogenesis and remodeling.

LITERATURE:
  1. Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol. Lee CY, Krimbou L, Vincent J, Bernard C, Larramée P, Genest Jr. J, Marcil M. Human Genetics 112: 552–562 (2003).
  2. New insights into the biogenesis of human high-density lipoproteins. Krimbou L, Marcil M, Genest J. Current Opinion in Lipidology 17: 258–267 (2006).
  3. Genetics of high-density lipoproteins. Dastani Z, Engert JC, Genest J, Marcil M. Current Opinion in Cardiology 21: 329–335 (2006).
Mon, Nov 13
“Mechanisms of long-term survival and evolution of bacteria”
Steven E. Finkel, PhD, Assistant Professor, University of Southern California, Department of Biological Sciences, Molecular & Computational Biology Program
Contact & Intro: Paivi Pajukanta
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ABSTRACT: My work focuses on the mechanisms bacterial cells use to survive long periods of stress, including limited nutrient availability and the action of oxidative damage agents. Furthermore, we study how populations experiencing stressful environments generate genetic diversity and adapt to those conditions. In other words, we are able to observe “evolution in a test tube” in real-time. One of the hallmarks of this genetic change is the appearance of mutants expressing the growth advantage in stationary phase (GASP) phenotype. GASP mutants have the ability to outcompete their unaged parents when mixed in co-culture. My presentation will describe the GASP phenomenon, provide several examples of the tremendous genotypic diversity generated in bacterial microcosms, and explore several mechanisms that microbes use to generate genetic diversity, possibly as a stress response.

LITERATURE:
  1. Long-term survival during stationary phase: evolution and the GASP phenotype. Finkel S. Nature 4: 113-120 (2006).
  2. Dps protects cells against multiple stresses during stationary phase. Nair S, Finkel S. Journal of Bacteriology 186: 4192-4198 (2004).
Mon, Nov 20
“Regulating the fate of developing hematopoietic stem cells”
Hanna Mikkola, MD, PhD, Assistant Professor, UCLA, Department of Molecular, Cell and Developmental Biology
Contact & Intro: Paivi Pajukanta
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ABSTRACT: Hematopoietic stem cells (HSC) can sustain life-long production of blood cells, as they possess unique abilities to self-renew and to differentiate into all blood cell lineages. De novo generation of hematopoietic stem cells from mesodermal precursors occurs early during fetal life, during which developing HSCs migrate through various fetal hematopoietic sites while maturing into functional adult type HSCs, expanding in number, and ultimately establishing their residence in the bone marrow. At all times, developing HSCs have to be protected from premature differentiation. Establishment and maintenance of “stemness” is regulated by interactions with the niche, i.e the microenvironment where HSCs develop and reside. Environmental cues are signaled to the nucleus, where various transcriptional regulators and epigenetic modifiers modulate gene expression, defining the ultimate function of the cell. We are pursuing to understand the complex regulatory mechanisms that govern self-renewal vs. differentiation decisions in HSCs. In order to understand how the microenvironment regulates HSCs during fetal life, we are investigating HSC development in the placenta, which we have recently identified as a novel hematopoietic site that harbors a large pool of HSCs during mouse development. To define the origin of placental HSCs, we used genetically modified mouse models for runx1, a transcription factor that is essential for HSC development in the embryo, and a Ncx1, a sodium calcium exchanger that is required for heartbeat and therefore circulation of blood cells. Our novel findings suggest that the placenta can indeed generate HSCs de novo, without input from circulating cells. Furthermore, it also serves as an important niche where HSCs expand and mature, without being expose for signals that would promote premature differentiation. Our parallel studies in human placentas suggest that also the human placenta can generate hematopoietic cells de novo, as the first hematopoietic cells were found in placental mesenchyme during first month of development, before circulating blood cells enter placental villi. Our future studies aim to define the microenvironmental cues that establish and maintain stemness in HSCs during ontogeny by studying various mouse models where HSC microenvironment is disrupted. Our goal is to identify the prerequisites for “stemness”, and exploit this knowledge to improve the in vitro microenvironment for culturing HSCs, which would hopefully ultimately allow us to generate functional HSCs from human embryonic stem cells.

LITERATURE:
  1. Transcriptional activators, repressors, and epigenetic modifiers controlling hematopoietic stem cell development. Teitell M, Mikkola H. Pediatric Research 59: 33-39 (2006).
  2. The journey of developing hematopoietic stem cells. Mikkola H, Orkin S. Development 133: 3733-3744 (2006).
  3. The placenta is a niche for hematopoietic stem cells. Gekas C, Dieterlen-Lièvre F, Orkin S, Mikkola H. Developmental Cell 8: 365–375 (2005).
Mon, Dec 04
“Genetic studies of hearing loss”
Heidi L. Rehm, PhD, Laboratory for Molecular Medicine, Harvard-Partners Center for Genetics and Genomics
Contact & Intro: Paivi Pajukanta
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ABSTRACT: My talk will focus on genetic studies of hearing loss. I will discuss our research on Norrie disease including the use of a mouse model to understand the pathophysiology of Norrie disease. In addition, I will discuss genotype-phenotype studies on hearing loss caused by mutations in Connexin 26. Finally, I will talk about the use of a Deafness GeneChip to advance molecular diagnostics for hearing loss.

LITERATURE:
  1. Vascular defects and sensorineural deafness in a mouse model of Norrie Disease. Rehm H, Zhang DS, Brown CM, Burgess B, Halpin C, Berger W, Morton CC, Corey DP, Chen ZY. The Journal of Neuroscience 22: 4286–4292 (2002).
  2. GJB2 mutations and degree of hearing loss: a multicenter study. American Journal of Human Genetics 77: 945–957 (2005).

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