 |
|
|
|
|
|
|
|
 |
|
||||||
 |
 |
 |
 |
 |
 |
 |
|
 |
|
||||||
|
|
|
|
|
|
|
|
|
|
||||||
|
|
|
|
|
|
|
|
|
|
||||||
From a global perspective, essential hypertension has become a modern-day scourge of pandemic proportions. Essential hypertension—which manifests as an abnormal and sustained elevation of blood pressure—is a major risk factor for death and disability from heart disease, stroke and kidney failure. It represents an enormous economic burden, with the cost of health care and prevention running into billions of dollars annually. Of the estimated billion
individuals afflicted worldwide, approximately half are unaware of their condition
and, among those with diagnosed hypertension, less than half are properly
controlled with drug therapy. Thus, the identification of environmental risk
factors and elucidation of the molecular and genetic underpinnings of essential
hypertension have been rigorously pursued for decades by many investigators,
with Dr. Pedro A. Jose at the forefront, among others.
Dr. Jose is an internationally recognized and highly esteemed scientist who
has distinguished himself for his contributions to the understanding of the
molecular mechanisms of dopamine receptor signal transduction and for his
pioneering work on several genetic models of hypertension. He is a preeminent
authority on developmental and pediatric nephrology and on the physiologic
ramifications of the peripheral dopaminergic system, a system that plays a
crucial role in regulating salt and water homeostasis by engendering natriuresis
at the proximal tubule and thick ascending limb of Henle.
Dr. Pedro A. Jose is Director, Center for Molecular Physiology Research, Children’s
National Medical Center and Professor of Pediatrics, George Washington University
School of Medicine and Health Sciences, Adjunct Professor of Physiology and
Biophysics at Georgetown University School of Medicine, Clinical Professor
of Cell and Developmental Biology and Anatomy, University of South Carolina
School of Medicine and Visiting Professor, Third Military Medical University
of the People’s Republic of China, Chongqing, P.R. China.
He received his M.D. (magna cum laude) in 1965 from the University
of Santo Tomas in Manila and topped the Philippine Medical Licensure Examination
on the same year. He performed his pediatric residency at SUNY Downstate Medical
Center and then pediatric nephrology fellowship at the Children’s Hospital
of DC and Georgetown University Medical Center. After his training, Dr. Jose
joined the faculty of Georgetown University School of Medicine as an Assistant
Professor in 1970 and, due to his prolific research output, he was quickly
promoted to Associate Professor of Pediatrics within 4 years. Concomitantly,
he received extra training in cardiovascular research and earned his Ph.D.
in Physiology in 1976 from Georgetown University, where he defended his dissertation
with distinction. He was conferred full Professorship in Pediatrics in 1983
and in Physiology and Biophysics in 1986.
Dr. Jose’s foray into the molecular mechanisms of essential hypertension
began in the 1980s while working in the laboratory of Dr. Philip. L. Calcagno
of the Department of Pediatrics and Dr. Gilbert M. Eisner of the Department
of Physiology and Biophysics at Georgetown University School of Medicine,
and Dr. Maral Mouradian at the National Institute of Neurological Disorders
and Stroke. As a pediatric nephrologist, his initial research focused on the
ontogenesis of the sympathetic control of renal function, the regulation of
AT1R; and AT2R receptors during ontogeny, and then the
mechanisms of dopamine D1 receptor defect in hypertension. Since then, Dr.
Jose’s research interests have extended into the entire panel of renal
dopamine receptors and their roles, interaction with, and regulation of other
key players of water and electrolyte balance. Ever on the lookout for useful
cutting-edge technology, he has applied novel molecular and biophysical techniques
to complement standard methods to further his research goals. With the advent
of genetic and genomic analyses of the human genome, he spearheaded cohort,
linkage and association studies to identify genetic risk factors and to determine
the epistatic combination of gene variants that predispose the most to hypertension
and salt sensitivity.
Dr. Jose and his research team showed
that ubiquitination of the EGF-tagged human angiotensin type 1 receptor (AT1R)
is initiated at the plasma membrane in human embryonic kidney-293 cells heterologously
expressing the human AT1R and human D5 dopamine receptor (D5R). In vehicle-treated
cells, AT1R (green) is mainly at the membrane but also in the cytoplasm. Ubiquitin
(blue) and the proteasome marker, p44S10 (red) are scattered throughout the
cytoplasm. The D5R agonist, fenoldopam, induces the co-localization of AT1R,
p44S10, and ubiquitin at the plasma membrane. The alterations in color indicate
co-localization: yellow=co-localization of AT1R and p44S10 (green+red); cyan=co-localization
of AT1R and ubiquitin (green+blue); magenta=co-localization of p44S10 and
ubiquitin (blue+red); white=co-localization of AT1R, ubiquitin, and p44S10
(green+blue+red). The merging of the line drawings, red, green, and/or blue
also depicts the co-localization of the different proteins. Scale bars are
shown in vehicle-treated cells.
Figure taken from: J.
Clin. Invest. 118(6): 2180-2189 (2008)
Throughout his career, he has forged extensive and fruitful collaboration
and alliances with national and international scientists. His significant
contributions toward the understanding of renal and extra-renal mechanisms
of blood pressure regulation include the functional and structural analyses
of the dopamine receptors in the various segments of the nephron, the development
and characterization of knockout mouse models for all of the dopamine receptor
subtypes, the molecular cloning of 5-HT7 serotonin receptor subtype, receptor-receptor
interaction, the elucidation of the role of the dopamine receptors on the
reactive oxygen species (ROS)-mediated hypertension, and the establishment
of select haplotypes that strongly associate with hypertension.
A major breakthrough in Dr. Jose’s career was the identification of
several single nucleotide polymorphisms (SNPs) in the gene encoding G protein-coupled
receptor kinase 4 (GRK4), i.e., R65L, A142V, A486V which strongly
associate with essential hypertension in several ethnic groups (Caucasians,
Chinese, Ghanaians, and Japanese), with predictive values that are higher
than those of other gene polymorphisms. The physiological significance of
GRK4 is underscored by it being the only gene postulated as causal of essential
hypertension that fulfills all the criteria needed to link a gene to a complex
disease. GRK4 induces the development of hypertension by causing the abnormal
post-translational modification of several dopamine receptors and increasing
the transcription of the angiotensin type 1 receptor. Dopamine receptors lower
blood pressure while angiotensin type 1 receptors increase blood pressure.
At present, transgenic mice harboring human GRK4 variants are the only rodent
models that develop hypertension due to variants of a single gene. This work
was awarded a US Patent (# 6,660,474), the 2003 Lewis K. Dahl Memorial Lecture
(Council for High Blood Pressure Research, American Heart Association), and
the 2007 Ernest H. Starling Distinguished Lecture (Water and Electrolyte Homeostasis
Section of the American Physiological Society)—two of the numerous national
and international honors and awards that Dr. Jose has received in recognition
of his significant contribution to science and society alike. Moreover, the
deciphering of the role of GRK4 gene variants in the pathogenesis of human
essential hypertension was recognized as the second “advance and discovery”
for the fiscal year cited by the Director of National Heart, Lung, and Blood
Institute (NHLBI) of the National Institute of Health (NIH) for its 2004 Budget
Justification to the US Congress.
Pedro A. Jose and his laboratory
celebrate his receiving the 2007 Ernest H. Starling Lecture Award from the
Water and Electrolyte Homeostasis Section of the American Physiological Society.
Dr. Jose has received more than US$ 35 million grant support, with two of
his current grants having been funded for more than 25 years. He currently
holds an NIH MERIT Award, two program project grants and two R01 grants. He
has authored more than 300 primary papers and reviews in top tier peer-reviewed
journals, which have received 4,900 citations worldwide, as well as more that
50 chapters in books, all of which have been well cited by other researchers
in the field. Dr. Jose is a highly admired speaker known for his expertise
and views, as well as for his humorous jokes delivered in his own inimitable
way. He has been very active in Georgetown University and has served in many
committees both from the Medical School and the University. He was President
of the American Society of Pediatric Nephrology, and has also held Offices
in several important scientific societies, as well as many Expert Panels and
Study Sections of the NIH. He has generously trained more than 50 pre- and
post-doctoral students, most of whom have excelled in their careers and have
maintained collaborative research with Dr. Jose.
The year 2009 marks another milestone in Dr. Jose’s successful career
when he was appointed Director of the newly established Center for Molecular
Physiology Research at Children’s National Medical Center in Washington,
DC. The Center was recently established to further our current understanding
of the genetic causes of human essential hypertension and salt-sensitivity
and, eventually, to develop diagnostic modalities and therapeutic strategies
that are tailor-made for the individual’s pharmacogenetic profile. Indeed,
Dr. Jose remains steadfast in his desire to help focus the future of healthcare,
in general, and the management of hypertension, in particular, to be predictive,
preventive, and personalized for the best outcome at the least cost.
BACK
TO TOP
