Recommendations for Future Research
I. Agenda
II. Recommendations from March 3, 2000 Afternoon Session
III. Recommendations from March 4, 2000 Morning Session
IV. Recommendations from March 4, 2000 Afternoon Session
V. Participants
VI. Additional Link
Thursday, March 2, 2000
6 p.m. | Registration - Pick up badges and programs - Versailles IV Opening Reception and Poster Session - Versailles IV Co-Chairs: Paul A. Watkins and Robert Katz |
7:00-7:30 p.m. | Reception |
7:30-8:30 p.m. | Viewing of posters |
8:30-9:30 p.m. | Viewing with authors by odd-numbered posters |
9:30-10:30 p.m. | Viewing with authors by even-numbered posters. (Posters will remain displayed through 10:00 p.m. on March 3.) |
Friday, March 3, 2000
7:30 a.m. | Continental Breakfast - Versailles IV |
7:55 a.m. | Oral presentations - Versailles III |
Morning Session : | Fatty acid uptake by and transport in the brain. Co-Chairs: Jacques H. Veerkamp and James A. Hamilton |
7:55 a.m. | Welcome. Paul A. Watkins (All presentations are 20 minutes long and are followed by a 5 minute Q & A session directly relevant to the presentation) |
8:00-8:25 a.m. | Structure of the microvascular endothelium. Lester R. Drewes |
8:25-8:50 a.m. | The diffusion mechanism in model and biological membranes. James A. Hamilton |
8:50-9:15 a.m. | Molecular barriers to lipid transport. Henry J. Pownall |
9:15-9:40 a.m. | A model of coupled fatty acid transport and metabolism. Jean A. Schaffer |
9:40-10:05 a.m. | The role of CD36 in fatty acid transport by various tissues. Nada Abumrad |
10:05-10:30 a.m. | Coffee break - Versailles IV |
10:30-10:55 a.m. | The role of membrane-associated proteins in cellular fatty acid uptake. Jan F. Glatz |
10:55-11:20 a.m. | Structural and functional properties of eight FABP types. Jacques H.Veerkamp |
11:20-11:45 a.m. | Mechanisms of fatty acid transport and targeting. Judith Storch |
11:45 a.m.-12:30 p.m. | Round table discussion and recommendations. Discussant: Alexander Leaf |
12:30-1:30 p.m. | Lunch - on your own |
Afternoon Session : | Brain uptake, transport and metabolism of PUFA: In vivo and in vitro studies. Co-chairs: Arthur A. Spector and Steven A. Moore |
1:30-1:55 p.m. | Sources of PUFA in the plasma. Arthur A. Spector |
1:55-2:20 p.m. | Measurement of brain PUFA uptake by perfusion techniques. Quentin R. Smith |
2:20-2:45 p.m. | NMR and isotope ratio MS studies of in vivo uptake and metabolism of PUFA by the rodent brain. Stephen C. Cunnane |
2:45-3:10 p.m. | PUFA transport and utilization in the developing brain. John Edmond |
3:10-3:40 p.m. | Coffee break - Versailles IV |
3:40-4:05 p.m. | PUFA synthesis, transfer and metabolism by brain-derived cells in vitro. Steven A. Moore |
4:05-4:30 p.m. | Lysophosphatidylcholine as a DHA carrier to the brain. Michel Lagarde |
4:30-4:55 p.m. | Uptake, synthesis and metabolism of PUFA by the retina and retina-derived cells in vitro. Robert E. Anderson |
5:00-5:45 p.m. | Round table discussion and recommendations. Discussant: Howard Sprecher |
Evening Session : | Workshop Dinner and Dinner Lecture - Washington Room Hosts: Paul A. Watkins and Robert Katz |
7:00-7:30 p.m. | Reception and cash bar |
7:30-9:30 p.m. | Dinner Dinner Speaker: Alexander Leaf "Reflections on the effects of polyunsaturated fatty acids on brain, heart and coronary heart disease" |
Saturday: March 4, 2000
7:30 a.m. | Continental Breakfast - Versailles IV |
8:00 a.m. | Oral presentations - Versailles III |
Morning Session : | The regulation and functions of DHA in neurons and neuronal membranes. Co-Chairs: Stanley I. Rapoport and Norman Salem, Jr. |
8:00-8:25 a.m. | The protective effect of DHA in neuronal apoptosis. Hee-Yong Kim |
8:25-8:50 a.m. | DHA accumulation and overaccumulation before birth. Impact on oxidative stress. Ephraim Yavin |
8:50-9:15 a.m. | The role of DHA-containing phospholipids in modulating G-protein-coupled signaling pathways: The visual transduction pathway. Burton J. Litman |
9:15-9:40 a.m. | Quantifying in vivo fatty acid signaling and turnover in the central nervous system. Stanley I. Rapoport |
9.40-10:10 a.m. | Coffee break - Versailles IV |
10:10-10:35 a.m. | Plasmalogens, phospholipases and DHA turnover. Lloyd A. Horrocks |
10:35-11:00 a.m. | Do DHA or other long-chain PUFA have gene regulatory roles? James M. Ntambi |
11:00-11:45 a.m. | Round table discussions and recommendations. Discussant: Robert E. Anderson |
11:45 a.m.-12:45 p.m. | Lunch - on your own |
Afternoon Session: | The roles of DHA in Zellweger syndrome, a representative peroxisomal biogenesis disorder. Co-chairs: Hugo W. Moser and Manuella Martinez |
12:45-1:10 p.m. | Normal and defective neuronal membranes: Structure and function. James M. Powers |
1:10-1:35 p.m. | The Zellweger syndrome animal model. Phillis L. Faust |
1:35-2:00 p.m. | The DHA deficiency animal model. Norman Salem, Jr. |
2:00-2:25 p.m. | Restoring DHA levels in the brains of Zellweger patients. Manuela Martinez |
2:25-2:45 p.m. | Coffee break - Versailles IV |
2:45-3:10 p.m. | DHA in other peroxisomal deficiency disorders. Hugo W. Moser |
3:10-3:55 p.m. | Round table discussions and recommendations. Discussant: Michael J. Noetzel |
4:00 p.m. | Adjournment |
Plasma sources of PUFA
Although data from serum lipid composition suggest that a potential major source of brain PUFA is lipoprotein-associated complex lipids, few studies have as yet addressed specific details of PUFA transport and uptake by this mechanism. Numerous lipoprotein classes and glycerolipid pools may be involved. Thus, investigations directed at the identification and functional characterization of PUFA-selective lipoprotein classes and PUFA-enriched glycerolipid pools would be enlightening. It may be possible to utilize stable PUFA isotopes (13C or perdeuterated) to identify and follow these lipoproteins/glycerolipids in feeding studies.
Role of barrier cells and astrocytes in the uptake and processing of PUFA or lipoprotein-associated PUFA
Studies that parallel the focus on serum lipid composition (particularly lipoproteins) should also be directed at cells carrying out barrier functions between blood and neurons. Foremost among these barrier cells are cerebral endothelium of the blood-brain barrier, choroid plexus epithelium that produce the bulk of cerebrospinal fluid, and astrocytes that closely associate with both cerebral blood vessels and neurons. The distribution, molecular nature, and function of lipoprotein lipase, lipoprotein receptors, and intracellular mechanisms for lipoprotein processing or trafficking in these cells are some of the major areas that require attention.
Once PUFAs are free of their carrier proteins and/or glycerolipids, a different group of binding and transport proteins are likely to be important in directing the flow of PUFA across barrier cells or within the brain. In this regard molecular and cell biological approaches should be aimed at understanding how fatty acid binding proteins (FABP) and fatty acid transport proteins (FATP) are distributed and how they function. Attention should also be directed at the specificity of enzymes that esterify PUFA, since the selectivity observed in membrane lipids may be regulated significantly at the esterification level.
Finally, additional carrier proteins or glycerolipids are likely to be involved in the intercellular distribution of PUFA within the brain parenchyma. For example, astrocytes are known to be a source of apolipoprotein synthesis in the brain, but little is known about the function of brain apolipoproteins in the intercellular exchange of PUFA. The fact that the E4 allele of apolipoprotein E is a major risk factor for Alzheimer's disease provides a significant allure to this area of study.
Local synthesis of PUFA
Although there is strong evidence for local synthesis of long-chain PUFA by brain-derived cells, recent advances in the molecular and cell biology of desaturase enzymes and peroxisomal assembly have yet to be applied systematically to the brain. The application of this new knowledge, particularly using genetic engineering approaches, should provide the clearest
evidence yet on the role of local synthesis in the accretion of PUFA by brain. It might also provide a basis for developing molecular approaches to therapy in neurological disorders where long-chain PUFAs are deficient.
Uptake rates of nutritionally supplied fatty acids by the brain
The method, model and "operational equations" presented at the workshop, for quantifying in vivo brain turnover rates and half-lives of fatty acids during uptake from plasma to the brain, can be applied to the elucidation of uptake rates of nutritionally -provided omega-6 PUFA (e.g. linoleic acid, LA; gamma-linolenic acid, GLA, arachidonic acid, AA), omega-3 PUFA (e.g. alpha-linolenic acid, ALA; eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) and of dietary saturated and monounsaturated fatty acids. In the case of saturated and monounsaturated fatty acids, studies could help clarify the possible differences between their uptake versus de novo synthesis in the developing and in the adult brains.
Effects of centrally acting drugs on the steady state of fatty acids
The above approach can also be applied to the assessment of changes in steady states in response to centrally acting drugs and pathological changes in bipolar and other disorders. When combined with neuroimaging intravenously injected radiolabeled PUFA can also be utilized to examine neuroplastic remodeling of brain fatty acids and lipid membranes.
Role of plasmalogens in glial and neuronal tissue
The role of DHA in the developing and adult brain
Intermediary metabolism of PUFA and brain disorders
Answers should be sought to questions involving post-uptake shuttling and metabolism of AA, EPA and DHA. Such questions are exemplified in the following: How does DHA, taken up by the brain through the BBB or synthesized from its precursors by astrocytic peroxisomes, reach its neuronal locations? Are there special DHA transporters in the brain? Are astrocytes mostly devoid of DHA and function primarily as elongation/ desaturation tools of EPA and its higher homolog docosapentaenoic acid (DPA)? What are the functions of EPA and DPA in astrocytes? Are EPA and DHA naturally segregated between astrocytes (EPA) and neurons (DHA)? What are the eicosanoids produced from EPA and what are their functions in the brain? What are docosanoids and what are their functions in the brain? Are these functions related to the pathophysiology of neuropsychobehavioral disorders such as: bipolar disorder, unipolar depression and schizophrenia? Do EPA, DPA and DHA exert the same therapeutic effect in these disorders? Etc.
DHA, EPA and apoptosis of glial and neuronal cells
-The finding that DHA can potentially inhibit neuronal apoptosis in two cell lines and that this inhibitory effect appears related to an increase in PS concentration raises several questions on yet another potential physiological role of DHA namely that of long-term survival of the neuronal cell. Does depletion of DHA result in neuronal death? If that effect of DHA is proven, is this effect reversible? Is there a connection between DHA depletion and the pathophysiology of inherited neurodegenerative diseases or Alzheimer's disease? Is the anti-apoptotic effect of DHA responsible for its apparent segregation to the neuron? What would be the consequences of long-term DHA storage in astrocytes, which appear to eliminate free DHA as it is formed from its precursors. How would the anti-apoptotic effect persist in animal models? All of these questions deserve to be answered.
Therapeutic interventions in peroxisomal biogenesis disorders
Understanding the functions of fatty acids in peroxisomal biogenesis disorders
The study of fatty acids in PBD disorders represents an important and promising field of investigation. The PBD disorders are associated with characteristic and severe handicaps and can be diagnosed early, including prenatally, by non-invasive and reliable diagnostic assays. Characteristic and striking abnormalities in fatty acid profiles and metabolism are present in all of these disorders. Some of these abnormalities can be normalized completely or in part, by dietary manipulations or by the administration of non-toxic natural compounds. Results on improvement in myelination of Zellweger patients following DHA supplementation therapy, over time, raises a slew of new questions. What is the mechanism by which DHA supplementation improves myelination? Since DHA is not abundant in white matter, is DHA present in oligodendrocytes where it exerts its effect indirectly through correction of reduced levels? Or rather does DHA lower VLCFA levels (which have been implicated in demyelination)? Does DHA raise plasmalogen levels known to be low in Zellweger syndrome thus protecting membranes from oxidative stress (see also recommendations in the March 4, 2000 Morning Session)? Animal models for most of these disorders are now available and new ones can be developed as needed.
Animal models for study of fatty acid function in glia and neurons
Omega-3 PUFA and the hepatic side of Zellweger syndrome
The peroxisomal defects of the Zellweger brain extend to the liver and kidney. The liver is known to be an important location for elongation and desaturation of alpha-linolenic acid (ALA) and other intermediates in the pathway to EPA and DHA. Several issues deserve further studies. For example: Is ALA elongated and desaturated in the livers of Zellweger patients? Is there partial production of DHA in the liver but not sufficient for satisfying needs? Can the existing animal models of Zellweger syndrome be used to develop methods that will allow a comparative assessment of plasma, erythrocyte and brain levels of EPA and DHA of healthy individuals and of Zellweger animal models? Could such methods be extended to other diseases of the central nervous system?
Nada A. Abumrad, PhD
Dept. of Physiology and Biophysics
SUNY at Stony Brook School of Medicine
Stony Brook, NY 11794-8661
516 444-3489
516 444-3432 (fax)
nadaa@physiology.pnb.sunysb.edu
Robert E. Anderson, MD, PhD
Oklahoma Center for Neuroscience
Univ. of Oklahoma Health Science Center
608 Stanton L. Young Blvd.
Oklahoma City, OK 73104
405 271-8250
405 271-8128 (fax)
robert-anderson@ouhsc.edu
Stephen C. Cunnane, PhD
Dept. of Nutrition Science
University of Toronto
Toronto, Ontario M5S 3E2
Canada
416-978-8356
416-978-5882 (fax)
s.cunnane@utoronto.ca
Lester R. Drewes, PhD
Dept. of Biochemistry and Molecular Biology
University of Minnesota School of Medicine
10 University Drive
Duluth, MN 55812-2496
218 726-7925
218 726-8014 (fax)
ldrewes@d.umn.edu
John Edmond PhD
Dept. of Biological Chemistry
UCLA School of Medicine
33-257 Center for Health Sciences
Los Angeles, CA 90095-1737
310-825-6535
310-206-5061 (fax)
jedmond@mednet.ucla.edu
Phyllis L. Faust, MD, PhD
Columbia University
Department of Pathology
630 West 168th Street
PH Stem 15?124
New York, NY 10032
212 305 7345
212 305 4548 (fax)
plf3@columbia.edu
Jan F.C. Glatz, PhD
Dept. of Physiology
Maastricht University
PO Box 616
NL-6200 MD Maastricht
The Netherlands
31-43-3881200
31-43-3884166 (fax)
glatz@fys.unimaas.nl
James A. Hamilton, PhD
Dept. of Biophysics
Boston Univ. School of Medicine
715 Albany St.
Boston, MA 02118-2394
617-638-5048
617-638-4041 (fax)
hamilton@med-biophd.bu.edu
Lloyd A. Horrocks, PhD
The Ohio State University
3145 Stoney Bridge Lane
Columbus, OH 43221-4913
614-777-8282
419-710-9465 (fax)
horrocks.2@osu.edu
Robert Katz, PhD
Omega-3 Research Institute, Inc.
3 Bethesda Metro Center, Suite 700
Bethesda, MD 20814
301-961-1918
301-417-9087 (fax)
omega3ri@aol.com
Michel Lagarde, PhD, DSc
INSA/INSERM
INSERM U 352,
Bioch. & Pharmacol. INSA-Lyon
20 Avenue Albert Einstein, B406
69621 Villeurbanne
France
33 472 43 82 40
33 472 43 85 24 (fax)
michel.lagarde@insa-lyon.fr
Alexander Leaf, MD
Harvard Medical School
Massachusetts General Hospital, East
149 13th Street
Charlestown, MA 02129
617-726-5908
617-726-6144 (fax)
aleaf@partners.org
Burton J. Litman, PhD
Lab. of Membrane Biochem. & Biophys.
NIH, NIAAA
Park Building, Rm 114
12420 Parklawn Drive
Rockville, MD 20852
301-594-3608
301-594-0035 (fax)
litman@helix.nih.gov
Manuela Martinez, MD
Hospital Materno-Infantil Vall D'Hebron
P. Vall D'Hebron 119-129
08035 Barcelona, Spain
34 93 4894065
34 93 4894064 (fax)
mmr@hg.vhebron.es
Steven A. Moore, MD, PhD
Dept. of Pathology
University of Iowa
Room 5239B RCP
Iowa City, IA 52242
319-384-9084
319 384-8053 (fax)
steven-moore@uiowa.edu
Hugo W. Moser, MD
Kennedy Krieger Institute
707 N. Broadway
Baltimore, MD 21205
410-502-9405
410-502-9839 (fax)
moser@kennedykrieger.org
Michael J. Noetzel, MD
Dept. of Pediatric Neurology
Washington Univ. School of Medicine
One Children's Place
St. Louis, MO 63110
314-454-6120
314-454-2523 (fax)
noetzel@kids.wustl.edu
James M. Ntambi, PhD
Dept. of Biochemistry
University of Wisconsin, Madison
433 Babcock Drive
Madison, WI 53706
608-265-3700
602-262-3272 (fax)
ntambi@biochem.wisc.edu
James M. Powers, MD
Dept. of Pathology
University of Rochester Medical Center
601 Elmwood Avenue
Rochester, NY 14642
716-275-3202
716-273-1027 (fax)
James_Powers@urmc.rochester.edu
Henry J. Pownall, PhD
Methodist Hospital
Baylor College of Medicine
6565 Fannin St. MS A-601
Houston, TX 77030
713-798-4160
713-798-5134 (fax)
hpownall@bcm.tmc.edu
Stanley I. Rapoport MD
Chief, Laboratory of Neuroscience
NIA, NIH
10 Center Drive, MSC 1582
Bethesda, MD 20892-1582
301-496-8970
301-402-0074 (fax)
sir@helix.nih.gov
Norman Salem, Jr. PhD
Lab. of Membrane Biochem. & Biophysics
NIAAA, NIH
12420 Parklawn Drive
Park Bldg., Room 114
Rockville, MD 20852
301-443-2393
301-594-0035 (fax)
nsalem@niaaa.nih.gov
Jean E. Schaffer, MD
Center for Cardiovascular Research
Washington University School of Medicine
660 S. Euclid Ave.
Box 8086
St. Louis, MO 63110-1093
314 362 8717
314 362 0186 (fax)
jschaff@imgate.wustl.edu
Quentin R. Smith, PhD
Dept. of Pharmaceutical Science
Texas Tech University HSC
School of Pharmacy
1300 Coulter Drive
Amarillo, TX 79106
806-356-4016
806-356-4034 (fax)
quentin@cortex.ama.ttuhsc.edu
Arthur A. Spector, MD
Dept. of Biochemistry
University of Iowa
4-403 BSB
Iowa City, IA 52242-1109
319-335-7913
319-335-9570 (fax)
arthur-spector@uiowa.edu
Howard Sprecher, PhD
Dept. of Medical Biochemistry
The Ohio State University
337 Hamilton
1645 Neil Ave.
Columbus, OH 43210-1218
614-292-4933
614-292-4118 (fax)
sprecher.1@osu.edu
Judith Storch, PhD
Dept. of Nutrition Science
Rutgers University
96 Lipman Drive
New Brunswick, NJ 08904
732-932-1689
732-932-3769 (fax)
storch@aesop.rutgers.edu
Jacques H. Veerkamp, PhD
Dept. of Biochemistry
University of Nijmegen
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
31-24-3614270
31-24-3540525 (fax)
J.Veerkamp@bioch.kun.nl
Paul A. Watkins MD, PhD
Kennedy Krieger Institute
707 N. Broadway
Baltimore, MD 21205
410-502-9493
410-502-8279 (fax)
watkins@kennedykrieger.org
Efraim Yavin, PhD
Weizmann Institute
76100 Rehovot
Israel
972-893-43095
972-894-60225 (fax)
ephraim.yavin@weizmann.ac.il
Last updated July 09, 2008