PAULINA NGUYEN HHMI RECIPIENT MENTOR: DR. GANESH CHERALA LAB: OSU-COLLEGE OF PHARMACY

 About 1 in every 12 babies in the United States is born with low birth weight  Increased risk for serious health problems such as lasting disabilities and even death.  Stunted growth  Higher incidence of diseases

 Poor conditions in the womb Greater susceptibility to diseases in adult life (Barker’s Hypothesis)  Low protein diet (LPD)–Rodent model for LBW Similar to human epidemiological findings LPD in rodent model can be manipulated in laboratory conditions

 Altered tissue development leads to altered development of organs such as in kidney and liver ◦ Affect renal organic transporter functionality ◦ Affects drug transport and excretion in and out of the body  LBW individuals will need different drug dosages

Low Birth Weight LPD Various Organs Heart, etc.

Drug Transport & Pharmacokinetics  Pharmacokinetics (PK) Study of how drug travels through the body o Absorption o Distribution o Metabolism o Excretion  Drug Metabolism and Transport Renal Excretion ADMEADME

Transporters OAT OCT PGP PEPT MRP Blood LUMEN BasolateralMembrane

 5 Organic Cation Transporters found in rat models 1.OCT1 2.OCT2 3.OCT3 4.OCTN1 5.OCTN2 OCT2 OCTN1 OCTN2

 Hypothesis Low birth weight, as a result of altered perinatal environment, leads to permanent alterations in the expression of renal OCT transporters.  Specific Aims  To quantify mRNA expression of r enal OCT2, OCTN1, and OCTN2 at various ages  To quantify protein expression of renal OCT2 at various ages

Study Design Birth weights noted; litters culled Control Low Protein (LP)

 Measure the mRNA level of OCT2, OCTN1, and OCTN2 expression in male and female offspring in both LP and Control groups using RT-PCR  Measure the protein expression of OCT2 in male and female offspring in both LP and Control groups using western blotting

◦ Samples from both LP and control groups:  Day 28 males and females  Day 65 males and females  Day 150 males and females  β-actin ◦ Positive control  Same sample used on all plates ◦ Negative Control  Nuclease-free H2O

* * *

* * * * Statistically Significant

Tissue Tissue Homogenate

 27 fold decrease in expression of OCT2 in Day 150 LP females relative to control (regular diet) females  Effect of LP diet seen in later life

 Sex hormone regulation of OCT2 a possible reason for 27 fold difference in LP Day 150 females  Sex hormone regulation of OCT2 Testosterone up-regulates expression of OCT2 Estrogen down-regulates expression of OCT2

 Howard Hughes Medical Institute  Cripps Funding  Cherala Lab ◦ Dr. Ganesh Cherala ◦ Barent DuBois ◦ Jacob Pearson ◦ Dr. Shobana Ganesan ◦ Tahir Mahmood ◦ Shawn Mahmood ◦ Alexandru Cioara  OSU-College of Pharmacy  Dr. Kevin Ahern

 Cherala G, Shapiro BH, and D'mello AP (2006) Two low protein diets differentially affect food consumption and reproductive performance in pregnant and lactating rats and long-term growth in their offspring. J Nutr 136: 2827–2833  Kathleen M. Giacomini, et al. (2010) Membrane transporters in drug development Nature Reviews Drug Discovery,  Hagenbuch, B (2010) Drug Uptake Systems in Liver and Kidney: A Historic Perspective Clinical Pharmacology & Therapeutics 87 1, 39–47