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Considering a career in translational research? Babbette LaMarca, Ph.D. Associate Professor, Thesis Director, Maternal Fetal Medicine Department of Pharmacology & Obstetrics & Gynecology University of Mississippi Medical Center, Jackson MS What is translational research? • Research that helps to make findings from basic science useful for practical applications that enhance human health and well-being. • "translate" findings in basic research quickly into medical practice and meaningful health outcomes “From bench to bedside” • From laboratory experiments to clinical trials to point-of-care patient applications. • All medicinal therapeutics came basic science that led to a paradigm shift Tool 1- Ask the right question • Be able to discern the difference between basic research performed “for the sake of knowledge” from what could become clinically relevant. Tool 2- Build a multi-skilled team • Research nurse, to identify patients and enroll them into a study • The physician to treat the patient and help with collection of samples • The researcher to process samples and either perform cell culture, run ELISA’s and process data and run statistics • Collaborate as a team to write the papers and communicate your science to the public Ongoing translational research at UMMC Could 17 OHP be a potential therapy for early gestational age diagnosed preeclamptics? Pregnancy-Induced Hypertension Characteristics Preeclamptic Women Hypertension + Proteinuria + Renal vasoconstriction + TPR/ CO + Endothelial dysfunction + Intrauterine growth restriction + TPR, total peripheral resistance. Preeclampsia is a major cause for prematurity • World wide-preeclampsia is responsible for up to 20% of the 13 million preterm births each year. • US-100,000 of the total 500,000 premature births annually Pathophysiology of preeclampsia Fig. 1. From SM Parikh & SA Karumanchi. Nature Med 2008 14, 810 – 812. Available at www.nature.com.proxygw.wrlc.org/nm/journal/v14/n8/full/nm0808810.html Placental cytokines are increased in preeclampsia 120 Placental IL-6 pg/ml 100 Placental sFlt-1 pg/ml 500 400 80 300 60 200 40 100 20 0 0 NP PE Normoxia (6%) NP PE NP Hypoxia (1%) 5 PE Normoxia (6%) PE Hypoxia (1%) Placental IL-10 pg/ml 4 3 LaMarca, unpublished data 2 1 0 NP NP PE Normoxia (6%) NP PE Hypoxia (1%) Leukocyte cytokine secretion is increased in preeclampsia LaMarca, unpublished data Preeclampsia is Associated with Chronic Immune Activation Chronic innate Inflammatory Response Normal Preeclamptic + +++ Monocytes, macrophages, T helper cells, and possibly NK cells T helper 17 cells + +++ FoxP3CD4+Treg Cells + ----- Endothelial dysfunction - +++ - +++ TNF alpha, IL-6, GM-CSF Activated immune cells ET-1, adhesion molecules, IL-8, MCP-1 AT1 and ETA autoantibodies Treatment options for Preeclampsia 1. I.V. infusion of magnesium sulfate is the therapeutic used for prevention of seizures during eclamptic events, (>32wks) Parameters measured by Doppler flow velocity in the uterine, umbilical and middle cerebral arteries significantly improved in severely preeclamptic women with Mag. Administration of MgSO4 significantly decreased systolic, diastolic and maternal blood pressure as well as decreased resistance index in uterine arteries 2. Labetalol and hydralazine are the basic anti hypertensives, calcium channel blockers are strong, alphamethyldopa and furosemide are used frequently, beta blockers are less frequent 3. ARBs, Etas and ACEi are never used. Several studies show that they cause fetopathy in RAS and renal development of baby. Progesterone attenuates TNF-α-stimulated ET-1 production Fig. 1. From Keiser et al. 2009 Am J Hypertension 22: 1120-1125. Available at ajh.oxfordjournals.org.proxygw.wrlc.org/content/22/10/1120.full Circulating progesterone is decreased in preeclamptic women Fig. 1. From Kiprono et al. Am J Obstet Gynecol 2013-04-30 Available at https://www-clinicalkeycom.proxygw.wrlc.org/#!/ContentPlayerCtrl/doPlayContent/1-s2.0S0002937813003451/ Potential use of 17 OHP for Preeclampsia? • 17-Hydroxyprogesterone is a natural progestin, produced mainly by the adrenal glands, gonads, and corpus luteum of the ovary • In pregnancy increases in third trimester due to the fetal adrenal production • 17-Hydroxyprogesterone Caproate is a synthetic hormone, similar in structure, interacts with the progesterone receptor • 17 OHP C is used to prevent subsequent preterm labor • Considered to be useful in patients diagnosed between 22-30 wks gestation Administration of progesterone on endothelial cell ET-1 secretion in response to PE serum 2 6 hours ET-1 (pg/ml) 1.5 Data from Kiprono et al. Am J Obstet Gynecol 2013-04-30 1 0.5 0 35 30 24 hours 25 ET-1 20 (pg/ml) 15 LaMarca, unpublished data 10 5 0 NP controls + P PE patients + P Progesterone blunts hypoxia stimulated cytokines and sFlt-1 Placental sFlt-1 expression 24hr Placental Explant Culture 300 5000 Normoxic Hypoxic 200 N = 4 patients 4000 Normoxic Hypoxic sFLT-1 (pg/mg/mL) IL-6 (pg/mg/mL) n=4 100 3000 2000 1000 0 0 0.1 uM 1 uM 0 10 uM 0 uM Concentrations of Progesterone 1 uM 10 uM Concentration of Progesterone 24hr Placental Explant Culture 24hr Placental Explant Culture 30 5 n=2-4 Normoxic Hypoxic 3 2 IL-17 (pg/mg/mL) n=5-6 p=0.051 4 TNF-alpha (pg/mg/mL) 0.1 uM 20 Normoxic Hypoxic 10 1 0 0 0 0.1 uM 1 uM Concentrations of Progesterone 10 uM 0 0.1 uM 1 uM Concentrations of Progesterone 10 uM LaMarca, unpublished data Administration of 17-OHP on MAP in response to placental ischemia or elevated TNF alpha or IL-6 Fig. 1. From Veillion, Am J Obstet Gyncol 2009, 201:324 Freely available at www.ncbi.nlm.nih.gov/pmc/article s/PMC2810642/ and Fig. 2. From Kiprono et al. Am J Obstet Gynecol 2013-04-30 Available at https://wwwclinicalkeycom.proxygw.wrlc.org/#!/Content PlayerCtrl/doPlayContent/1-s2.0S0002937813003451/ Fig. 2, top. From Keiser et al. 2009 Am J Hypertens 22: 1120-1125. Available at ajh.oxfordjournals.org.proxygw.wrlc.or g/content/22/10/1120.full * p=0.059 LaMarca, unpublished data 17 OHP decreases pathophysiology associated with hypertension during pregnancy Administration of 17 OHP decreased circulating levels of TNF alpha and IL-6 in RUPP rats Fig. 3. From Veillon Jr. et al. Am J Obstet Gynecol 2009, 201(3):325.e1325.e6. Available at www.ncbi.nlm.nih.gov/pmc/articles/P MC2810642 Progesterone decreases TNF alpha stimulated renal ET-1 Fig. 3A. From Keiser. et al. Am J Hypertens 2009, Oct 22(10)11201125. Available at www.ncbi.nlm.nih.gov/pubmed/1974 5821 Administration of 17 OHP decreased circulating levels of AT1-AA in IL-6 infused rats 20 15 LaMarca, unpublished data AT1-AA bpm 10 5 0 NP IL-6 NP+17OHP IL-6+17OHP Half of Science is Serendipity • Progesterone attenuates TNF alpha induced ET-1 secretion. • Administration of progesterone decreased endothelial cell activation in response to serum from PE women • Administration of progesterone (1uM) significantly blunts hypoxia stimulated inflammatory cytokines and sFlt-1 from placental explants • Administration of 17 OHP decreased blood pressure in response to RUPP or elevated TNF alpha or IL-6 during pregnancy • Administration of 17 OHP decreased circulating cytokines in RUPP rats, local ET-1, and circulating AT1-AA in response to IL-6 infusion Skill sets to acquire • 1. Learn to interpret the data and ask clinically relevant questions • 2. How can that data be applied to a pathophysiological condition • 3. Communicate your data and ideas with physicians and discuss a potential collaboration and clearly define the clinicians role in the research Skill sets to acquire • 4. Build your research team • 5. Submit your IRB and start collecting samples • 6. Communicate with your team regularly with data updates and writing the papers and grants. Your communication with the practicing physician and nurses is key to successful translational research Translational research is the key to improving quality of patient care