The RCMI Translational Research Network (RTRN) is pleased to announce the recipients of the Small Grants Program (SGP) Pilot Project award for the 2013 to 2014 cycle, ending on June 30, 2014. The RTRN SGP Pilot Project provides funding for short-term basic, clinical and translational science projects that involve inter-institutional collaborations and mentoring between faculty at two or more RCMI grantee institutions and that utilize specific services of the Data Coordinating Center (DCC).

Principal Investigator: Dr. Saguna Verma, University of Hawaii at Manoa

Collaborators: Dr. Qiyi Tang, Ponce School of Medicine and Dr. Methode bacanamwo, Morehouse School of Medicine

Mentor: Dr. Yasuhiro Yamamura, Ponce School of Medicine

Saguna Verma, Ph.D., University of Hawaii at Manoa

Dr. Saguna Verma’s long-term goal is to develop effective therapies for flavivirus-associated neuroinvasisve disease. The objective of her collaborative resarch is to investigate the role of histone deacetylases (HDAC) in flavivirus neuropathogenesis. Her research uses both, in vitro and in vivo mouse models to delineate various innate immune signaling pathways that contribute to inflammation and neuronal death in flavivirus infections.

Dr. Verma stated, “My application builds logically on my previously published studies on the association of inflammation with neuronal death and blood-brain barrier disruption. It is research aligned with the focus of RTRN, which is to support basic science research with translational potential.”

The expected results from this high-impact study will delineate a novel signaling pathway associated with West Nile Virus (WNV) encephalitis and will be the basis of her future NIH grant application to use HDAC inhibitors as a much-needed therapeutic strategy to ameliorate the devasting consequences of WNV neuroinvasive disease.

Principal Investigator: Dr. Lily K. Cheung, Texas Southern University

Mentor: Dr. Pratibha V. Neurukar, University of Hawaii at Manoa

Lily K. Cheung, M.D., Texas Southern University

Having more than 10 years of experience in biomedical research in laboratories, as well as 20 years of experience in Clinical Pharmacy and Clinical Pharmacokinetics Practice, Dr. Lily K. Cheung has positioned herself to conduct the project, entitled “Pharmacokinetic/Pharmacodynamic Study of Metformin with Gastric Bypass Surgery”, which requires both clinical and biomedical laboratory knowledge and skills.

According to Dr. Cheung, knowledge about the effect of gastric bypass surgery on medications, specifically metformin, is currently lacking and this lack of knowledge may lead to inappropriate dosing and potentially compromised clinical outcomes for these individuals. Additionally, racial and gender disparities have been demonstrated in this extremely obese population, with the highest prevalence reported among non-Hispanic Black women.

Dr. Cheung shared her appreciation for the excellent guidance provided by her mentor, Dr. Pratibha V. Nerurkar from University of Hawaii at Manoa, during the preparation of her SGP application. “I relish RTRN’s effort in fostering collaborative research among RCMI member institutions and faculty members, and I also appreciate the strong support from DCC.”

Principal Investigator: Dr. Michelle M. Martinez-Montemayor, Universidad Central del Caribe

Collaborator/Mentor: Dr. Suraganie Darmhawardhame, University of Puerto Rico Medical Sciences Campus

Michelle M. Martinez-Montemayor, Ph.D., Universidad Central del Caribe School of Medicine

“Our lab studies inflammatory breast cancer (IBC) and diabetes cellular biology and potential natural therapeutics for these intractable diseases,” said Dr. Michelle M. Martinez-Montemayor, “My long-term goal is to lead independent research programs to identify molecular targets and develop effective strategies for the prevention and treatment of breast cancer and diabetes.” Dr. Martinez-Montemayor’s research is based on two of her publications on the role of Reishi in IBC progression. Her research aims to elucidate molecular mechanisms of IBC invasiveness, focusing on the role of inflammatory cytokines and their involvement in the manifestation of an atypical inflammatory reaction leading to tumor spheroid formation.

 

 

Principal Investigator: Dr. Richard J. Noel, Jr., Ponce School of Medicine

Collaborator/Mentor: Dr. Valerie Wojna, University of Puerto Rico Medical Sciences Campus

Richard J. Noel, Jr., Ph.D., Ponce School of Medicine

Dr. Richard J. Noel, Jr. is an Associate Professor and director of the RCMI-sponsored Molecular and Genomics Core. He has over 15 years of molecular biology experience, including over ten while employed at the Ponce School of Medicine. His research interests include the role of HIV proteins in the development of neuropathology using cell culture and rat animal models. In addition, he has broad experience in studying SIV viral evolution in rhesus macaques in a drug abuse setting. Dr. Noel’s Pilot Project, entitled “Role of hypocretin/orexin system in HIV-associated neurocognitive disorders,” aims to define the underlying cause of elevated hrct/ox levels in the cerebrospinal fluid (CSF) of HIV-seropositive patients with HIV-associated neurocognitive disorders (HAND), which significantly decreases quality of life. According to Dr. Noel the study is innovative since it focuses on the effects that HIV infection may have on the hcrt/ox system, and the role that this system may have in HAND.

Small Grant Program Pilot Project Abstracts are listed below:

 

Dr. Saguna Verma

Epigenetic regulation of innate immune responses to flaviviruses

West Nile Virus (WNV) causes potentially lethal encephalitis in almost 1-2% of febrile patients. Inflammatory response initially triggered to clear WNV promotes additional damage resulting in neuronal death, however, the associated mechanisms are unclear. A potential approach for improving disease outcome focuses on regulating inflammatory processes induced by neurotropic viruses. The objective of this study is to characterize the role of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in regulating WNV-induced inflammatory cytokines. Our overall hypothesis is that chromatin remodeling via changes in the HDACs and HATs activity is a critical step in the regulation of the host inflammatory response to WNV infection. In Aim 1 we will be determine the specific HDACs that respond to WNV infection in mouse bone marrow-derived macrophages (BMDMs) and Aim 2 will utilize a pharmacological and genetic approach to block specific HDACs by using HDAC inhibitors and siRNA and evaluate the production of multiple Th1/Th2 cytokines following WNV infection in BMDMs. Together these studies will provide mechanism-based evidence for the role of specific HDACs in WNV-associated inflammation and may identify novel targets for new generation therapeutics for patients infected with WNV.

 

Dr. Lily K. Cheung

Pharmacokinetic/Pharmacodynamic Study of Metformin with Gastric Bypass Surgery

Bariatric surgery has been the only durable option for weight loss in the extremely obese individuals. The number of bariatric surgery performed has increased 10-fold from 1998-2008. Roux-en-Y gastric bypass surgery (GBS) is the most frequently performed bariatric surgery procedure in the US. It involves restrictive and malabsorptive mechanisms. Theoretically, GBS will significantly alter the absorption/disposition of orally administered medications. Currently, littel information is available about the effect of GBS the absorption/disposition of metformin. The lack of this knowledge may result in inappropriate dosing and compromized clinical outcomes. Thus, the goal of this study is to compare the pharmacokinetic/pharmacodynamic (PK/PD) properties of metformin before and after GBS. To accomplish this goal, the hypothesis that PK/PD profiles of metformin are decreased after GBS will be tested. Adults who undergo GBS and take scheduled metformin prior to GBS will be included in the study. Blood samples will be drawn immediately prior to surgery and at each follow-up visit at 1,3,6,12 months after the surgery. Serum drug concentrations will be determined using LC-MS/MS and pharmacokinetic parameters will be calculated. The pharmacodynamic profiles, i.e. glucose concentrations and HGA1c levels will also be determined.

 

Dr. Michelle M. Martinez-Montemayor

Role of cytokines in inflammatory breast cancer invasion modulated by Reishi

Inflammatory Breast Cancer (IBC) is the most lethal form of breast cancer with a survival rate of <5% in 5y. IBC symptoms include erythema, breast-swelling, pain, and “peau d’orange”. However these symptoms are associated with the presence of tumor spheroids, which are non-adherent cell clusters that invade the breast dermal lymphatics. IBC manifestation may suggest an atypical involvement of immunological and inflammatory processes. Interleukin-6 (IL-6) is a cytokine that initiates inflammation, and the immune response. Cancer cells exposed to or that secrete IL-6 autocrinely display increased invasion. IBC cells secrete IL-6 and express IL-6 receptors, however the autocrine regulation of this cytokine has not been studied in IBC. Our laboratory’s research interests are focused on tumor biology and on the effects of Ganoderma lucidum (Reishi) as a natural IBC therapeutic. Reishi disintegrates tumor spheroids, and reduces IL-6 secretion. The hypothesis is that Reishi inhibits IBC tumor progression by inhibition of the IL-6 autocrine signaling loop, and by modulation of cytokine secretion. Specific aims are: 1) To study the contribution of IL-6 in the invasive potential of IBC cells and to determine how Reishi modulates it in vitro. 2) To delineate Reishi effects in invasion impairment via cytokine modulation in vivo.

 

Dr. Richard J. Noel, Jr.

Role of hypocretin/orexin system in HIV-associated neurocognitive disorders
HIV-positive patients live longer, however approximately 50% of the HIV-infected population acquires HIV-associated neurocognitive disorders (HAND) which significantly decreases quality of life. In order to help the HIV-positive population it is necessary to find plausible biomarkers for further understanding of the pathophysiology of HAND in chronically infected subjects. Hypocretin, also known as orexin, is a neurotransmitter associated with alertness. It also regulates sleep, appetite, energy consumption, and recently it has been associated with addictive behavior. Data from our laboratory shows hcrt/ox CSF levels were higher in HIV-seropositive women from the Hispanic/Latino Longitudinal Cohort (HLLC) when compared with controls and that is was associated with HAND. Suggesting the possibility that hcrt/ox system my have a role in the pathopysiology of HAND and serve as a biomarker for HAND. The goal of this proposal is to define the underlying cause of elevated hrct/ox levels in the CSF of HIV-seropositive patients with HAND. For the purpose of this study we will use HIV-seropositive brain tissue from individuals with and without HAND from the National NeuroAIDS Tissue Consortium (NNTC). We propose the following aims: Aim 1: To determine if HIV infection alters the presence or activity of hcrt/ox –producing neurons in the lateral hypothalamus (LH) in HIV-seropositive individuals with and without HAND. Hcrt/ox neurons are localized in the LH. We hypothesize that the increased hcrt/ox levels in CSF of HIV+ patients is due to increased release of hcrt/ox from LH neurons. Aim 2: To determine if HIV-infection alters the presence of hcrt/ox receptors in the hippocampus in HIV-seropositive individuals with and without HAND. The significance of this study lies in determining the role that the hcrt/ox system plays in HAND. Hcrt/ox CSF levels could serve as a biomarker for early detection of HAND aiding the HIV-infected individual to start early treatment. This study is innovative since it focuses on the effects that HIV infection may have on the hcrt/ox system, and the role that this system may have on HAND.