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Laboratory
research is the vital component of the biological sciences since
they are empirical disciplines. Without laboratory work, a biological
scientist can not succeed. My research projects have continued to
make excellent progress here at Seton Hall University. I would like
to state that all of my achievements could not have happened without
the encouragement and collaboration of my Biology colleagues and
Seton Hall’s administration. I am especially indebted to my
research group, including my undergraduate and graduate students,
research assistants, post-doc fellows, and collaborators because,
without them, my successful research progress would not be possible.
My research project has been funded by the National Institutes of
Health (grant number DA 07058) since 1992, and was successfully
renewed in March 1997 for five years. A renewal application of this
award has been submitted for review at the current time. This grant
support is the centerpiece of all my research-related activities.
A.
Areas of Research
The
overall goal of my research-in-progress is to delineate the effects
of chronic opiate exposure on the penetration of the HIV-1 virus
through the vascular endothelial cell (VEC) barrier in the immune-challenged
individual. Although the VEC is effective at inhibiting penetration
of most viruses, ample evidence has shown that the VEC fails to
stop the invasion of HIV-1. Bacterial pathogens, which stimulate
the production of the immunocytokine, interleukin-1-beta (IL-1ß),
can also breach the blood-brain barrier (BBB) and invade the central
nervous system (CNS) via paracellular and transcellular mechanisms.
During the period since my last promotion application, we have shown
that chronic morphine exposure potentiates
IL-1ß-mediated leukocyte-endothelial adhesion (LEA), thus,
potentially promoting the transcellular migration of leukocytes
across the VEC barrier. Morphine stimulates the hypothalamic-pituitary-adrenal
(HPA) axis through activation of mu opioid receptors (MOR); whereas
we have shown that chronic morphine inhibits IL-1ß-induced
secretion of anti-inflammatory HPA products. Taken together, these
data led us to hypothesize that opioid-dependent and IL-1ß-dependent
pathways converge intracellularly; thus, morphine use, combined
with inflammation, enhances the permeability of the vascular endothelial
cell barrier, leading to increased penetration of HIV-1. Due to
the limitations of the biological laboratory facilities at Seton
Hall University, the HIV-1 work as described will be conducted via
a collaborative setting with Dr. Jean Bell at the University of
Edinburg in Scotland. The following specific aims and studies are
designed to test our hypothesis.
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Specific
Aim 1:
To
investigate the convergence of MOR- and IL-1 receptor-mediated pathways
in vitro by determining if:
1.
Morphine or IL-1ß modulates the activity of FOS in IL-1ß
receptor positive Madin-Darby canine kidney (MDCK) cells stably
transfected with MOR (designated MDCK-MOR1 cells).
2.
Morphine or IL-1ß modulates the activity of NFkB in MDCK-MOR1
cells.
3.
Treatment with morphine modulates MOR and IL-1ß receptor (IL-1R)
expression in MDCK-MOR1 cells.
4.
Treatment with IL-1ß modulates MOR and IL-1R expression in
MDCK-MOR1 cells.
Specific
Aim 2:
To
characterize how opiate-dependent pathways are altered by bacterial
and viral immune challenges in vivo by determining if:
1.
Cytokines, such as IL-1ß, tumor necrosis factor-alpha (TNF-alpha),
and interleukin-6 (IL-6), alter MOR expression and the levels of
the endogenous opiate peptides, such as ß-endorphin and endomorphin,
in the rat.
2.
The bacterial endotoxin, lipopolysaccharide (LPS), alters MOR expression
and endogenous opiate peptide levels in the rat.
3.
There is a difference in expression of MOR and endogenous opiate
peptide levels in uninfected versus HIV-1-infected post-mortem brain
tissue.
Specific
Aim 3:
To
explore chronic morphine’s effects on bacterial-induced inflammation
in vivo at the molecular, cellular, and systemic levels by
determining if:
1.
Morphine alters the LPS-induced plasma levels of pro-inflammatory
molecules, such as IL-1ß, TNF-alpha, and IL-6, and anti-inflammatory
agents, such as corticosterone, in the rat.
2.
Morphine alters LPS-induced leukocyte-endothelial cell adhesion
(LEA) and white blood cell flow (FLUX) in the rat.
3.
Morphine promotes the progression of LPS-induced inflammation in
response to endotoxin shock.
Specific
Aim 4:
To
delineate the effects of chronic morphine exposure and LPS-induced
inflammation on the permeability of the vascular endothelial cell
(VEC) barrier by determining if:
1.
Morphine, LPS, or the combination of morphine and LPS enhances the
permeability of the VEC barrier using an in vitro VEC barrier culture
model.
2.
Morphine, LPS, or combined morphine and LPS increases HIV-1 penetration
of an in vitro VEC barrier model.
3.
There is a difference in CD68 immunoreactivity, a marker for infiltrating
macrophages, in post-mortem brain tissue from HIV-1-infected individuals
with and without opiate use.
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B.
Grant Support
Title: |
Morphine
Actions on the Immune System |
PI: |
Sulie
L. Chang, Ph.D. |
Type: |
RO1
(DA07058; Years 12-16) |
Period: |
February
1, 2002 to January 31, 2007 |
Agency: |
National
Institute of Drug Abuse |
Total
cost: |
$1,084,000.00
including 70% indirect cost based on salary and wage |
Title: |
Morphine
Actions on the Immune System |
PI: |
Sulie
L. Chang, Ph.D. |
Type: |
RO1
(DA07058; Years 1-11.) |
Period: |
February
1, 1992 to January 31, 2002 |
Agency: |
National
Institute on Drug Abuse |
Total
cost: |
$655,909
with 70% indirect cost based on salary and wages |
Title: |
Program
Enhancement for Molecular and Cellular Biology at Seton Hall
University |
Group
leader: |
Sulie
L. Chang, Ph.D. |
Period: |
September
1, 2001 to June 30, 2002 |
Agency: |
New
Jersey Commission on Higher Education |
Total
direct cost: |
$100,000 |
This
is a $100,000 research instrumentation grant to pay, in part, for
the following equipment: (1) Cytofluor 4000 Fluorescence Multi-Well
Plate Reader w/ Temp. Control: (2) Fluorescent imager, and (3) ABI
Prism 7000 Sequence Detection System. Not only will this funding
provide the state-of-the-art tools needed so that my research project
will further progress, but, as Chair of Biology, this will also
allow me to continue to strengthen the research facilities and activities
of the Department of Biology in order to enhance our recruitment
competitiveness for both faculty and students.
Title: |
National
Institute on Drug Abuse Summer Research Replacement for Undergraduates
|
PI: |
Sulie
L. Chang, Ph.D. |
Type: |
Administrative
supplemental (DA07058-07S1) |
Period: |
June
1, 1998 to August 10, 1998 |
Agency: |
National
Institute on Drug Abuse |
Total
direct cost: |
$3,672.00
with 8% indirect cost based on stipend |
Title: |
National
Institute on Drug Abuse Summer Research Replacement for Undergraduates
|
PI: |
Sulie
L. Chang, Ph.D. |
Type: |
Administrative
supplemental (DA07058-08S1) |
Period: |
June
1, 1999 to August 10, 1999 |
Agency: |
National
Institute on Drug Abuse |
Total
direct cost: |
$6,042.00
with 8% indirect cost based on stipend |
As
a National Institute on Drug Abuse (NIDA) RO1 award grantee, I am
eligible to accept NIDA Summer Research Replacement awards for undergraduates.
The above listed two grants were two administrative supplements
to support Bernardo Felix and Jenine Anday, two minority students,
who did research work in the summers of 1998 and 1999, respectively.
Following their summer research in my laboratory, both Jenine Anday
and Bernardo Felix decided to continue to pursue a Master’s
degree in the Department of Biology at Seton Hall University.
Title: |
National
Institute on Drug Abuse Research Supplements for Under-Represented
Minorities |
PI: |
Sulie
L. Chang, Ph.D. |
Type: |
Administrative
supplemental (DA07058-08S2) to support Bernardo Felix’s
grad. study |
Period: |
January 1, 1999 to August 31, 2000 |
Agency: |
National
Institute on Drug Abuse |
Total
direct cost |
$64,796.00
with 8% indirect cost based on salary |
Title: |
National
Institute on Drug Abuse Research Supplements for Under-Represented
Minorities |
PI: |
Sulie
L. Chang, Ph.D. |
Type: |
Administrative
supplemental (DA07058-08S2) to support Jenine Anday’s
grad. study |
Period: |
February
15, 2001 to December 31, 2001 |
Agency: |
National
Institute on Drug Abuse |
Total
direct cost |
$20,042.00
with 8% indirect cost based on salary |
As
a National Institute on Drug Abuse (NIDA) RO1 award grantee, I am
also eligible to apply for supplemental support for under-represented
minorities for their graduate study in my laboratory. The above
listed two grants are funding to support Bernardo Felix and Jenine
Anday while working on their Master’s degree in my laboratory.
Bernardo Felix is now a Research Associate at Merck, Inc., and Jenine
Anday is a Doctoral degree student at the University of Connecticut
Medical School.
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C. Research Related Professional Presentations
1.
Presentations of papers at meetings:
•
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Sulie
L. Chang, Nilesh A. Patel, Erich L. Vidal, and Milan Fiala
(1997) “Glucocorticoid suppression of cytokine-induced
adhesion of HL-60 human promyelocytic leukemia cells to cultured
human endothelial cells” (1997) Society for Neuroscience,
New Orleans, LA |
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Sulie
L. Chang (2000) “Chronic exposure to morphine affects
the neuroendocrine-immune axis” 62nd Annual
Meeting of the Committee on Problems in Drug Dependence (CPDD),
San Juan, Purto Rico |
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Sulie
L. Chang (2000) “Impact of cocaine on chemokine receptor-driven
HIV neurovasion” 62nd Annual Meeting of the
Committee on Problems in Drug Dependence (CPDD), San Juan, Purto
Rico |
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Yuhui
Jiang, Carla Klowdesky, and Sulie L. Chang (1999) “Endomorphin-1
and endomorphin-2 induce the expression of FOS-immunoreactivity
in the rat brain”, 7th Annual Symposium on
Neuroimmune Circuits and Infectious Diseases, Young Investigator
Award Presentation, Bethesda, MD |
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Homaira
Rahimi, Bernardo A. Felix, Yuhui Jiang, Jenine A. Patel, and
Sulie L. Chang (1999) “Morphine potentiates lipopolysaccharide-induced
cytokine production by HL-60 human leukemia cells”, 7th
Annual Symposium on Neuroimmune Circuits and Infectious Diseases,
Bethesda, MD |
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Bernardo
A. Felix, Jenine A. Anday, Steven D. House, and Sulie L.
Chang (2000) "Synergistic effects of morphine and lipopolysaccharide
endotoxin on the permeability of inulin across a microvascular
endothelial cell barrier in vitro", 62nd Annual
Meeting of the Committee on Problems in Drug Dependence, San
Juan, Purto Rico |
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Yuhui
Jiang, Steven D. House, and Sulie L. Chang (2000) "Adrenalectomy
alters leukocyte-endothelium interactions in rat mesenteric
venules following systemic treatment with lipopolysaccharide
(LPS) and acute inflammation induced by N-formyl-methionyl-leucyl-phenylalanine
(FMLP)", 62nd Annual Meeting of the Committee
on Problems in Drug Dependence, San Juan, Purto Rico |
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Carla
M. Klodesky, Yuhui Jiang, Horace H. Loh, and Sulie L. Chang
(2000) “Ethanol induction of FOS immunoreactivity in mu
opioid receptor knock out mice” 31st Meeting
of the International Narcotics Research Conference. |
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Tezeta
Roro, Jessica M. Mitchell, Maria MacWilliams, and Sulie L.
Chang (2000) “Induction of multiple drug resistance
in Bacteria” Project SEED Conference, American Chemical
Society. |
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Sulie
L. Chang, Bernardo A. Felix, Jenine K. Anday, and Milan
Fiala (2000) “Morphine enhances permeability across vascular
endothelial cell barriers” 30th Annual Meeting
of the Society for Neuroscience. |
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Xin
Mao, Jitesh A. Patel, Jenine K. Anday, WenXin Li, and Sulie
L. Chang (2001) "Mu Opioid Receptor Mediated LPS-induced
Cytokine Secretion by Human Promyelocytic Leukemia HL-60 cells"
8th Annual Meeting of Society of NeuroImmune Pharmacology
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Jenine
K. Anday and Sulie L. Chang (2001) “ Morphine induced
apoptosis in endothelial cells: FAS/FAS-L dependent?”
8th Annual Meeting of Society of NeuroImmune Pharmacology
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Jenine
K. Anday, Bernardo A. Felix, Steven D. House, Sekhar Gujuluva,
Milan Fiala, and Sulie L. Chang (2001) “Morphine
enhances the permeability across endothelial cell barriers”
12th Annual Research Colloquium of School of Graduate
Medical Eduction, Seton Hall University. |
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Debbie
BAlkaran and Sulie L. Chang (2001) “Apoptosis of
endothelial cells affects HL-60 cell adhesion” Project
SEED Conference, American Chemical Society. |
2.
Invited speaker at symposia (1998 to 2001):
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Sulie
L Chang (1998) “Cocaine affects hemodynamics in rat”
6th Annual Symposium on Drugs of Abuse, Immunomodulation,
and AIDS, Scotsdale, AZ |
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Sulie
L. Chang (1998) “Lipopolysaccharide (LPS) increases
the expression of mesenteric mu opioid receptor and plasma levels
of endomorphin-1” 29th Meeting of International
Narcotic Reference Conference, Garmish, Germany. |
• |
Sulie
L. Chang (1999) “Endotoxin shock and opioid dependent
pathways” 7th Annual Symposium on Neuroimmune
Circuits and Infectious Diseases, Bethesda, MD |
• |
Sulie
L. Chang (2000) “Impact of cocaine on chemokine receptor-driven
HIV neuroinvasion” at the 62nd Annual Meeting
of College on Problems of Drug Dependence, St. Juan, Puerto
Rico. |
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Sulie
L. Chang (2000) “Morphine affects the neuro-immune
axis and enhances the permeability across the vascular endothelial
cell barriers” 62nd Annual Meeting of College
on Problems of Drug Dependence, St. Juan, Puerto Rico. |
• |
Sulie
L. Chang (2001) “Mu opioid receptor potentiates LPS-induced
cytokine secretion in HL-60 cells” 8th Annual
Meeting of the Society of NeuroImmune Pharmacology, Atlanta,
GA. |
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Sulie
L. Chang (2001) “Chronic exposure to morphine affects
the neuroendocrine-immune axis” 32nd Annual
Meeting of International Narcotic Reference Conference, Helsinki,
Finland. |
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