National CTSA Consortium
Accelerating Discoveries Toward Better Health
The National Center for Advancing Translational Sciences funds the national CTSA program. Visit CTSACentral.org to find out more!
Accelerating Discoveries Toward Better Health
The National Center for Advancing Translational Sciences funds the national CTSA program. Visit CTSACentral.org to find out more!
The Milan Criteria is used as the basis for selecting patients for liver transplantation in treating early liver cancer or cirrhosis. Even though Milan is the accepted standard of care with a five-year survival rate of 80% and less than 15% recurrence rate, utilization of better predictors would improve the survival and recurrence rates. This project uses miRNAs isolated from liver tumors to produce a novel biomarker system that characterizes 67 miRNAs that can distinguish patients with and without recurrent liver cancer. These data will provide a novel basis for improving use of valuable liver transplant resources.
We are delaying publishing the synopsis of Dr Maquat’s project for intellectual property reasons.
Loss of synaptic function in Parkinson’s Disease (PD) has been linked to genetic pathways and may be related to mitochondrial dysfunction. Specifically, numerous mutations in PINK1 indicate a direct involvement of this gene in PD pathogenesis. Using mice with PINK1 deletion, this project will use electron microscopy to determine ultrastructural changes in mitochondria of dopaminergic neurons, and whether a small molecule or gene-based inhibition of Drp1 restores mitochondrial abnormalities and attenuates synaptic dysfunction in a mouse model of nigrostriatal dysfunction.
The primary goal of this project is to provide preliminary validation of a novel, fluorescence-based high-throughput screen (HTS) for compounds able to selectively bind CUG repeat RNA. Data resulting from this effort will be used as preliminary data in an NIH application focused on preclinical development of candidate therapeutic agents for type 1 Myotonic Dystrophy (DM1), and will set the stage for a more extensive HTS effort in which larger libraries will be probed.
There is no effective chemotherapy to treat recurrent or inoperable meningiomas. Current research demonstrates that available Akt inhibitors slow meningioma growth in vitro, however, are toxic. Protease inhibitors have been in use for years as anti HIV therapeutics, have anti-proliferative activity, and may inhibit Akt activation. This project determines the capacity of several anti-HIV protease inhibitors to inhibit the Akt pathway and stimulate the apoptosis pathway in meningioma cells in vitro.
Many cardiac etiologies can lead to congestive heart failure (CHF), including hypertension, coronary artery disease, infections, and genetics. A common compensatory mechanism in CHF is cardiac hypertrophy, which often leads to cardiac failure. BAT1 and Bcr are targets that have been identified as key regulators of protein synthesis and cardiac myocyte hypertrophy. This project utilizes the Gene Targeting and Transgenic Core to establish two transgenic mice that will determine the role of BAT1 in cardiac hypertrophy and cardiac failure.
Brain attack, or stroke, is a major contributor to morbidity and mortality in the US. Despite advances, treatment interventions are lacking that diminish damage or can protect neurons from damage. Recently, iron chelators have demonstrated neuroprotective properties against stroke in anima studies. HIF-1 induction was a likely target for chelators, however, HIF-1 knockout experiments did not indicate that HIF-1 targets mediated neuroprotection. This project utilizes the Functional Genomics Center to identify candidate genes that are targets for neuroprotection by iron chelators.
Infants are particularly susceptible to influenza infection and are a significant proportion of the yearly 1 million influenza deaths worldwide. There are limited data regarding the vaccination of premature infants and infants under the age of two, which are at greatest risk of contracting influenza infection. Currently there are two influenza vaccine types available: trivalent, inactivated influenza vaccine (TIV) and live, attenuated influenza vaccine (LAIV). This project seeks to determine the immunogenicity of these vaccine types in children 24-30 months of age to provide important data for subsequent clinical trials in infants less than two years of age.
Obesity in children ages 6-18 years has tripled in the last 20 years. Inherent in this obesity group is an apparent increased risk for type 2 diabetes and cardiovascular disease. In adults, metabolic syndrome (MS) are a cluster of different characteristics of lipid values, glucose, blood pressure and waist size directly associated with type 2 diabetes and cardiovascular events. Smoking and waist size are also risk factors associated with MS in adults. This project seeks to identify the risk for MS and cardiovascular risk in children
Many medications alter bone metabolism, including selective serotonin reuptake inhibitors (SSRIs). Patients beginning SSRI therapy for depression are at possible risk for bone loss. This project will demonstrate if a collagen biomarker detects decreases in bone formation in women undergoing SSRI therapy. If successful, this collagen biomarker may help monitor bone health during SSRI therapy, assess need for alternative therapies, and indicate bone loss in clinical trials of novel therapeutics.
Up to 70% of extremely low birth weight infants develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by protracted need for supplemental oxygen. These infants continue to have pulmonary infections, wheezing and emphysema as they mature into adulthood. The molecular pathogenesis of BPD is poorly understood and, despite advances in NICU care, treatment is supportive and based upon the hope that the infants will outgrow the disease. To advance the field, this project utilizes the Functional Genomics Core Laboratory in determining expression profiles of lung samples from BPD infants and controls.
Prenatal exposure to mercury, lead, or lack of maternal iron can result in hypomyelination that can lead to lower IQs, impaired verbal skills, and behavioral abnormalities. Chemotherapy with 5-fluoruracil can result in myelin disruption and damage. The project seeks to utilize the auditory brainstem response (ABR) as a tool to detect early demyelination changes prior to the onset of clinical symptoms.
Development of an effective HIV vaccine has been elusive, due, in part to the inability to generate neutralizing antibodies to HIV-1. In rare cases, some patients develop virus-neutralizing antibodies directed against conserved antigenic epitopes on the virus envelope - including the CD4 binding site. To date, conventional immunization approaches have proven ineffective at eliciting such antibodies in healthy subjects. This project seeks to use a novel technology to produce discontinuous antigenic mimics (or "mimotopes") of the virus-neutralizing epitope within the CD4 binding site of HIV-1 Env, with the goal of using these mimics as part of a future HIV-1 vaccine.
β-catenin and bone morphogenic protein-2 (BMP-2) are two proteins principally involved in bone formation during embryogenesis and bone fracture repair as adults. Understanding the mechanisms of bone fracture repair with age can lead to development of drug intervention strategies for treating defects in bone healing or accelerate bone repair in aging humans. This project develops two conditional β-catenin and BMP-2 transgenic mouse models using the Gene Targeting and Transgenic Core Laboratory.
In order for viral replication of influenza A, a trimeric complex consisting of viral proteins, PA, PB1, and PB2 must occur. Drugs that interfere with developing this complex or disrupting this complex have the ability to prevent or reduce the symptoms of influenza. This project utilizes the High Throughput Screening Core to screen chemical libraries for novel molecules that are capable of disrupting this influenza complex.
Platinum-based chemotherapy, one of the most common therapeutics for cancer, results in a 5-year survival rate of over 95% of men with testicular cancer. However, platinum can be detected in serum for up to 20 years after the completion of chemotherapy, representing a patient population continually exposed to this heavy metal. This project correlates known adverse effects associated with platinum-based chemotherapy to long-term Pt exposure, with a focus on cardiovascular risk.
ERK5 is a MAP kinase, which plays a significant role in cell growth and differentiation, although emerging evidence suggests unique functional characteristics of cardioprotective and anti-atherosclerotic function of ERK5 activation. This project utilizes the Universities’ High Throughput Screening Core to identify small molecules that could activate ERK5, and prevent cardiac damage after myocardial infarction and the development of atherosclerosis formation.
Many anti-cancer therapies exhibit cardiotoxic effects. This project uses cardiac magnetic resonance imaging to identify changes in myocardial tissue characterization in patients undergoing anthracycline chemotherapy. Establishing these changes will allow for determining early signs of cardiotoxicity and the ability to predict which patients will develop severe, irreversible cardiac toxicity
Long QT Syndrome, or LQTS, refers to a prolonged QT interval of the EKG and is associated with syncope, arrhythmias, and sudden cardiac failure. LQTS’s mechanism is due to altered potassium ion channels which delays repolarization of the heart prior to the next beat. Genetic mutations in ion channels link family members to LQTS and the project investigates SNP polymorphisms in subunit proteins among many family members utilizing the Functional Genomics Center.
Intracellular Ca2+ transients are essential for proper cardiac development. Deletion of genes responsible for Ca2+ transients result in embryonic hearts that never beat or have abnormal morphology. The Universities’ Multiphoton and EM Core Laboratories will be utilized in this project to visualize mitochondria during cardiac development in mouse embryos. These studies will provide insights into the role of calcium signaling and mitochondrial biogenesis in regulating normal cardiac morphogenesis, in causing congenital heart defects, and in the etiology of cardiac diseases.
Huntington’s Disease is an incurable, neurodegenerative disease involving the medium spiny neurons (MSN) of the striatum. Injury to the MSN is related to a mutation in the Huntington gene (Htt), which causes the progressive decay of MSN. This project utilizes the Functional Genomics Core Laboratory to identify signaling pathways that are involved in the neurotoxicity of mutant mHtt on human MSN.
The etiology of prostate cancer progression from the non-tumorigenic state to tumorigenic state to metastasis is largely unknown. Genetic changes in tumors are recognized, however, protein changes as a result of the tumorigenic to metastasis mutations are problematic and largely unknown. This project will utilize the Proteomics Core Lab to determine whether up or down regulated proteins can account for phenotypic differences in the progression of prostate cancer to the metastasis state. Identification of protein changes can also identify targets for therapeutic interventions.
Human survival against infectious agents has succeeded because of antibody generation and response by memory B-cells. Drs. Sanz and Wei have identified many novel subpopulations of B-cells that establish a strong association between certain memory B-cell subsets and active immune responses. This project seeks to utilize the Functional Genomics Center to determine gene expression profiles of these memory B-cell subsets to provide the supporting data for a competitive Program Project Grant that examines the function and regulation of memory B-cells in several disease states.
Prostate cancer is the most common malignancy in men and the second-leading cause of cancer-related deaths. A novel theory that prostate cancer stem cells (PCSCs) survive conventional therapy explains why prostate cancer may reemerge as androgen independent and treatment refractory. Dr. Huang has identified a sub-population of prostate tumor cells that possess characteristics of PCSCs. This project seeks to target cell surface molecules that would inhibit proliferation and differentiation of PCSCs, and when combined with conventional therapy, may eliminate prostate cancer entirely.
This project identifies the molecular basis for susceptibility to human papillomavirus infection, which can range from benign lesions to malignant neoplasms. HPV is a major STD, with 80% of the sexually-active population being HPV exposed at some point in their lifetime. Identifying host biological factors would predict those at greatest risk for HPV infection and malignant disease.
Elevated potassium levels are potentially dangerous and can be life threatening. Normally, renal excretion handles excess potassium; however, dietary sources and ACE-inhibitors can elevate potassium into the lethal range. There is an apparent adrenal component for this regulation as adrenalectomy abolishes this regulation. This project will analyze unique blood proteins isolated from rats fed high potassium diets.
Pregnancy represents an environmental change (physiologic, hormonal, and behavioral) to the mother and identifies a time when genes can be activated/inhibited as a result of these changes. Maternal weight gain and post-pregnancy weight retention has been associated with the 825T allele of the GNB3 gene, which is important in the regulation of body fat. The 825T allele is also associated with low birth weight babies, has a high prevalence (72%) in African-American women, and, in non-pregnant carriers - is responsive to physical activity to limit weight increase. This project identifies the 825T allele in African-American mothers and the T haplotype effects on excessive maternal weight gain, post-partum weight retention, physical activity, and low birth weight.
It is well known that Influenza infection targets the young and old with high morbidity and mortality. Dr O’Reilly has developed a transgenic mouse that allows for ready identification of a novel subpopulation of lung alveolar Type II cells that proliferate with Influenza exposure, but do not differentiate into Type I cells. This project will validate 20 genes unique to these Type II cells that have been previously identified by microarray data to have anti-microbial and anti-viral effects and other genes involved in maintaining stem cell populations. Identification of genes that control these vital lung cells will provide novel therapeutic strategies against life-threatening Influenza and other respiratory pathogens. Click here to view Dr. O'Reilly's profile.
Despite the fact that anti-HIV treatments are allowing HIV-infected patients live longer, HIV-associated cognitive impairment remains a frequent comorbidity. Using the new MALDI-TOF/TOF instrument in the proteomics center (URPC), this project will analyze 30 specific proteins induced and isolated from HIV-infected patients treated with Minocyline. Minocycline has both anti-inflammatory and neuroprotective effects and may provide treatment cues for prevention of cognitive impairment in HIV-infected patients.
This project investigates whether a novel inhibitor of thrombin, BIBT 986, is effective in the treatment of pulmonary arterial hypertension (PAH), a devastating disease with few effective therapies. If BIBT 986 prevents progressive obliteration of pulmonary arterioles in rats, then this thrombin antagonist would introduce a novel treatment for PAH that could be quickly translated to humans.
Bladder tumors recur in about half of all bladder cancer patients within the first two years of initial diagnosis. The high rate of recurrence necessitates life-long intensive monitoring. There is compelling evidence in the literature for clonal, oligoclonal, and multi-focal origins for recurrent bladder cancer. Using the state-of-the-art 500K SNP array analysis in the Functional Genomics Core Lab, a genome-wide SNP analysis of index and recurrent tumors would determine a clonal relationship and lay the foundation for prognosis and therapy decisions.
This is a pilot study examining the role of the antioxidant, 15-epi-lipoxin, a bioactive lipid mediator that may be associated with a cardiac protective effect in ischemic cardiomyopathy and ventricular arrhythmias. The LSC will support the genetic testing for 3 SNPs (single nucleotide polymorphisms) associated with the lipoxygenase promoter and 5-lipoxygenase activating protein. Genetic variation could impact fatty acid metabolism and indicate a risk for ventricular tachycardia, ventricular fibrillation, and sudden cardiac death.
The objective of this project is to identify genes that are controlled by estrogen responsive elements as a therapeutic means of treating breast cancer. One third of breast cancer cases fail to respond because of loss of estrogen receptors, and other cases acquire resistance to the anti-estrogens or anti-aromatases. Using a synthesized molecule (invented by Dr Muyan) that bypasses the ERE-genes and restores estrogen receptor function, is a novel treatment strategy that could provide breast cancer treatment in cases that are otherwise resistant to therapy. The LSC will fund RT-PCR experiments that confirms data from encouraging gene array experiments conducted thus far.
This project is an adjunct to complement a series of other assays in a funded K23 award (Pietropaoli, PI) that identifies estrogen in reducing the morbidity and mortality in severe sepsis. Specifically, the LSC will fund the assays for determining the role of arginine metabolism: ADMA (naturally occurring NOS inhibitor) and four amino acids (arginine, ornithine, citrulline, and proline) in patients with severe sepsis.
This project examines the toxicity of PPARγ inhibitors, which have been recently identified by Dr Schaefer to have chemotherapeutic actions on colorectal cancer, a leading cause of cancer-related deaths in the U.S. This proposal introduces a novel treatment for colorectal cancer that could be of enormous therapeutic value, when traditional treatment modalities are no longer effective.