Babbette LaMarca, Ph.D. Associate Professor, Thesis Director, Maternal Fetal Medicine Department of Pharmacology & Obstetrics & Gynecology University of Mississippi Medical Center, Jackson MS Considering a career in translational research?

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?

Preeclamptic Women Hypertension + Proteinuria + Renal vasoconstriction + TPR/ CO + Endothelial dysfunction + Intrauterine growth restriction + Pregnancy-Induced Hypertension Characteristics 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 , 810 – 812. Available at html

Placental cytokines are increased in preeclampsia Placental IL-6 pg/ml NP PE Hypoxia (1%)Normoxia (6%) Placental sFlt-1 pg/ml NP PE Hypoxia (1%)Normoxia (6%) Placental IL-10 pg/ml NP PE Hypoxia (1%)Normoxia (6%) LaMarca, unpublished data

Leukocyte cytokine secretion is increased in preeclampsia LaMarca, unpublished data

PreeclampticNormal Activated immune cells Monocytes, macrophages, T helper cells, and possibly NK cells T helper 17 cells Chronic innate Inflammatory Response TNF alpha, IL-6, GM-CSF Endothelial dysfunction ET-1, adhesion molecules, IL-8, MCP-1 AT1 and ETA autoantibodies Preeclampsia is Associated with Chronic Immune Activation FoxP3CD4+Treg Cells

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 MgSO 4 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 Am J Hypertension 22: 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 Available at com.proxygw.wrlc.org/#!/ContentPlayerCtrl/doPlayContent/1-s2.0- S /

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 wks gestation

Administration of progesterone on endothelial cell ET-1 secretion in response to PE serum NP controls PE patients NP controls PE patients + P 24 hours 6 hours ET-1(pg/ml) ET-1(pg/ml) Data from Kiprono et al. Am J Obstet Gynecol LaMarca, unpublished data

Progesterone blunts hypoxia stimulated cytokines and sFlt-1 LaMarca, unpublished data

Administration of 17-OHP on MAP in response to placental ischemia or elevated TNF alpha or IL-6 * p=0.059 Fig. 1. From Veillion, Am J Obstet Gyncol 2009, 201:324 Freely available at s/PMC / and Fig. 2. From Kiprono et al. Am J Obstet Gynecol Available at clinicalkey- com.proxygw.wrlc.org/#!/Content PlayerCtrl/doPlayContent/1-s2.0- S / Fig. 2, top. From Keiser et al Am J Hypertens 22: Available at ajh.oxfordjournals.org.proxygw.wrlc.or g/content/22/10/1120.full LaMarca, unpublished data

AT1-AA bpm Administration of 17 OHP decreased circulating levels of AT1-AA in IL-6 infused rats NPIL-6 NP+17OHPIL-6+17OHP 17 OHP decreases pathophysiology associated with hypertension during pregnancy Fig. 3. From Veillon Jr. et al. Am J Obstet Gynecol 2009, 201(3):325.e e6. Available at MC Fig. 3A. From Keiser. et al. Am J Hypertens 2009, Oct 22(10) Available at Administration of 17 OHP decreased circulating levels of TNF alpha and IL-6 in RUPP rats Progesterone decreases TNF alpha stimulated renal ET-1 LaMarca, unpublished data

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 Half of Science is Serendipity

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

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. Skill sets to acquire

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