Faculty

Paloma Giangrande

Paloma Giangrande, PhD

Principal Investigator
Associate Professor of Internal Medicine, Division of HOBMT
Abboud Cardiovascular Research Center
Associate Professor of Radiation Oncology
Molecular and Cellular Biology (MCB)
Free Radical and Radiation Biology
Medical Scientist Training Program (MSTP)
Toxicology Program member

Faculty Profile

PDF icon​Curriculum Vitae

Contact Information

Office: MERF 5202 
Phone: (319) 384-3242
Email: paloma-giangrande@uiowa.edu


Post Doctoral Fellows

Sven Kruspe, pPhD

Sven Kruspe, PhD

Post Doctoral Research Fellow 

sven-kruspe@uiowa.edu 

Research Interests: My research focuses on the development of diagnostic and therapeutic nucleic acids. Two classes of nucleic acids are part of my projects: 
Aptamers - In my research I make use of aptamers binding to specific cancer cell markers, such as PSMA, the prostate specific membrane antigen. Various ways arise of how such an aptamer can be harnessed as a therapeutic means: It could either block a binding site for a ligand or an active site of an enzymatic activity. It could also act in a stimulating manner by induction of a conformational change or dimerization of the target antigen. Or eventually the aptamer might be taken up into the cancer cell, hence opening up possibilities of using it as a delivery vehicle for tethered drug molecules, e.g. a tumor suppressing siRNA. Nucleic acid probes for the detection of circulating tumor cells. Metastatic cancer is aside from cardiovascular diseases the leading cause of deaths in the United States and the developed countries in general. Early identification of cancer patients, e.g. breast cancer or pancreatic cancer, at greatest risk of developing metastatic disease is thus an important goal that would enable oncologists to aggressively treat these patients while the cancer is still vulnerable. Despite the implications of CTCs as diagnostics for advanced breast cancer treatment, a critical challenge for adopting CTC-based diagnostic tests has been the development of methods with sufficient sensitivity to reliably detect the small number of CTCs that are present in the circulation. Furthermore, current tests for CTC detection are expensive, have high false positives and negatives, have high background noise, are time consuming and require a significant level of expertise to conduct. To overcome the limitations of current CTC detection assays and develop more sensitive, rapid and cost effective CTC detection methods, I am exploring the potential of detecting CTCs by measuring their nuclease activity with nuclease-activated probes. These probes make use of specific nucleases being present within or even secreted by CTCs. The design and improvement of these probes in terms of specificity and sensitivity as well as the development of their applicability in a study on breast cancer patients are part of my most recent research.


Ofonime Udofot, PhD

Ofonime Udofot, PhD

Post Doctoral Research Fellow 

ofonime-udofot@uiowa.edu

Research Interests: My research interest lies in the fields of nanobiology and drug delivery. My research efforts will address a critical unmet need in the treatment of various critical diseases such as Prostate cancer and hyperproliferative/inflammatory cardiovascular disease. To achieve this, I will seek effective ways in delivering and increasing the bioavailability of RNA bio-drugs with fewer side effects. My goal is to work towards the development of next-generation smart drugs with improved efficacy and reduced toxicity. As a Postdoctoral Research Scholar in Dr. Paloma Giangrande’s laboratory, I will be concentrating on the development and delivery of RNA bio-drugs for the treatment of cardiomyopathy associated with sepsis and also prostate cancer. These studies will evaluate these novel RNA bio-drugs in cells in culture as well as in animal models of inflammation and prostate cancer. Finally, I will evaluate and optimize formulations for enhancing delivery and bioavailability to target the cardiovascular tissues and prostate cancer site. 


Graduate Students

Kevin Urak

Kevin Urak, MS

Graduate Research Assistant
Molecular and Cellular Biology Graduate Program

kevin-urak@uiowa.edu 

Research Interests: Multiple organ dysfunction syndrome (MODS) is an insidious and life threatening sequelae in patients suffering major trauma or illness. With prompt care patients with major trauma/illness can survive the initial injury, but soon other organs not directly affected by the original injury/illness may become dysfunctional. Breathing problems will develop that require placement on a ventilator, the kidneys will stop working requiring dialysis, and the patient will bleed from every orifice. Coordinated efforts in the intensive care unit (ICU) may reverse MODS at great cost, but there is currently no treatment to prevent MODS. Of those that develop MODS (200,000 case/year in the US), the risk of death is 40%. The most common organ involved in MODS is the lung (referred to as acute respiratory distress syndrome or ARDS). Trauma, smoke inhalation, burns, radiation, severe infection and blood transfusions can each cause ARDS and lead to acute lung injury (ALI). Only recently have investigators recognized that there is a common element to these conditions: damaged tissues releasing histones into the circulation. Histones are basic proteins found in chromatin. They normally reside in the nucleus of the cell and partner with DNA. However, when released from dying cells, histones have toxic effects on the lungs and other organs. We hypothesized that neutralization of extracellular histones with nucleic acid aptamers (anionic molecules) can prevent the morbidity and mortality associated with MODS/ARDS. We have employed Systemic Evolution of Ligands by Exponential Enrichment (SELEX) technology to identify RNA aptamers that bind with high affinity (low nM-pM range) and specificity to those histones (H3 and H4) known to cause MODS/ARDS but not to other proteins present in blood or on cells. We confirmed that histones H3/H4 induce pronounced platelet aggregation, which can be inhibited with the addition of the selected RNA aptamers. Furthermore, we demonstrate that histone-induced cytotoxicity can be reversed by treatment with the RNA aptamers both in vitro (lung-derived endothelial and epithelial cells) and in vivo in a mouse model of MODS/ARDS. Current efforts are focused on evaluating and the efficacy and safety of these RNA bio-drugs in other established murine models of MODS/ARDS (e.g. inhalation lung injury and influenza). In conclusion, we present robust preclinical data on a novel class of therapeutics against circulating histones that may be potentially effective in a wide-variety of common clinical conditions with high degree of morbidity, mortality and expense and for which, there is currently no effective treatment thus, establishing a paradigm change in the treatment of critically ill patients.


Research Staff

Giselle Blanco

Giselle Blanco, MS

Research Assistant

giselle-blanco@uiowa.edu

Research Interest: I manage the Giangrande Lab, and assist in the different projects.


Li-Hsien Lab, PhD

Li-Hsien Lin, PhD

Associate Research Scientist

li-hsien-lin@uiowa.edu

Research Interest: Histones are one of damage-associated molecular pattern molecules that can amplify tissue injury by killing other cells in addition to their agonistic activity. Studies have shown that extracellular histones are mediators of multifunctional organ dysfunction (MODS) and acute respiratory distress syndrome (ARDS). Patients who survive major injury often develop MODS and/or ARDS, which results in devastating psychological and physical morbidity and high mortality rate. Currently, there is no FDA approved therapy to prevent the effect of histones and patients can only rely on supportive care. The development of selective inhibitors of histone-mediated injury is a unique opportunity to interrupt the pathophysiologic cascade. Aptamers are short, single-stranded DNA or RNA molecules that are selected for binding to a specific target. They are analogous to antibodies in their range of target recognition and variety of applications. They possess several key advantages over their protein counterparts in that they are self-refolding, redox-insensitive, and they tolerate pH and temperatures variation. They also are easier and more economical to produce and have a long shelf life. The clinical potential of aptamers is encouraged by the FDA approval of an aptamer-based drug for macular degeneration and by clinical trials that demonstrate the safety and efficacy of systemically administered RNAs. We are working on pioneering RNA aptamers that would bind to extracellular histones and prevent their toxic effects in vitro and in vivo.