Published May 31, 2018
UB’s Clinical and Translational Science Institute (CTSI) has awarded new grants that support promising translational research projects in Western New York.
Using local institutional support and an award from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, the CTSI funded 11 projects in the 2018-19 cycle involving researchers from the Jacobs School of Medicine and Biomedical Sciences and Buffalo Translational Consortium partner institutions.
The pilot studies program provides seed money to help advance new technologies and therapeutics from the conceptual stage to clinical studies. Having preliminary, proof-of-concept studies in hand greatly enhances a proposal’s chance of attracting outside funding for further testing.
“In addition to supporting innovative, high-impact, clinical-translational science, the program looks for projects that foster cross-disciplinary collaborations and mentoring relationships,” says Steven J. Fliesler, PhD, UB Distinguished Professor and Meyer H. Riwchun Endowed Chair Professor of ophthalmology and co-director of the Translational Pilot Studies Program.
“Priority is given to projects that address health care disparities in underserved populations in Western New York and allow applicants to generate sufficient preliminary data to secure future extramural funding,” adds Fliesler, a Research Career Scientist at the VA Western NY Healthcare System.
Following are summaries of the 2018-19 CTSI Translational Pilot Studies Program awards:
Lead poisoning continues to be an important public health problem and requires effective solutions. Children with elevated blood lead concentrations (BLLs) are more likely to be from non-white families, low socioeconomic status backgrounds and urban centers.
These same communities are also more likely to consume nutritionally inadequate diets and develop nutrient deficiencies, some of the most important risk factors for elevated BLLs. There is widespread perception that diet can be used to manage elevated BLL in young children, based on recommendations from the Centers for Disease Control and Prevention (CDC).
But the evidence base behind these recommendations is incomplete, uncertain or simply unavailable. Furthermore, diet can be a source of exposure to other toxic chemicals, such as pesticides. Any dietary recommendations should take into account potential unintended consequences.
Leveraging data from the U.S. National Health and Nutrition Examination Survey, the research team will investigate the potential of dietary approaches to lower BLLs in toddlers and young children who are highly susceptible to lead toxicity.
The study has two specific aims:
The recommendations for observing patients after administering naloxone for opiate overdose are inconsistent. To address this, the project will build upon and validate a promising decision rule, which to date has not been widely accepted, by performing a large observational, multicenter study.
The Hospital Observation Upon Reversal with Naloxone (HOUR) study seeks to validate a six-step approach that would allow emergency physicians to safely discharge patients after a one-hour observation period following naloxone administration for opiate overdose.
The hypothesis of the study is that physicians can safely release a patient after a one-hour observation period if the patient can mobilize as usual with normal oxygen saturation, respiratory rate, heart rate, temperature and Glasgow Coma Scale score.
The performance of the decision rule will be evaluated based on the presence or absence of any of the predetermined endpoints, which include repeat naloxone administration, artificial ventilation and death.
The results of this study, combined with a parallel project examining emergency department-initiated buprenorphine for opiate addiction, will be leveraged to seek funding for a rapid transition to treatment protocol.
The long-term goal is to improve the social and health outcomes of patients suffering from substance abuse disorder.
Patients with lung cancer on Medicaid or who have no insurance experience worse outcomes than other patients. There are approximately 1,504 new lung cancer cases in the Western New York counties each year.
Understanding the relationship between access to health care and related outcomes among the most disadvantaged patients requires comprehensive data and a multidisciplinary analytic approach.
The researchers propose the following specific aims:
The goal of the study will be to compare health utilization of low-income lung cancer cases with evidence-based guidelines for lung cancer and lay the groundwork for improving access to care and long-term health outcomes for rural and urban cancer survivors.
The study will take advantage of existing data resources to better understand lung cancer in WNY, and it will generate substantial data to inform models of care for rural and urban communities aimed at tackling the inequities of care and increased burden of disease faced by Medicaid-insured individuals with a diagnosis of cancer.
Myelodysplastic syndrome (MDS) is a slow-growing leukemia (AML) that is associated with aging. Most patients come to medical attention because they have low blood counts and the diagnosis is made after a doctor performs a bone marrow biopsy and evaluation of the blood.
Patients with MDS who need treatment for their low blood counts receive a type of low dose chemotherapy called hypomethylating agents.
The two approved drugs in this class are called decitabine and azacitidine, and they are believed to work by tricking cancer cells into turning back on important signals that the cancer cell has been ignoring or has turned off in order to grow faster.
Among the genes that get turned back on by the action of decitabine is NY-ESO-1. Some cancers turn this gene on, and when they do, the immune system can see it and can attack these cancer cells. Immune recognition of this gene in cancer is associated with slower cancer growth.
The researchers showed that MDS and AML patients getting decitabine turn on NY-ESO-1 in their cancer cells. They also showed that when cancer cells turn this gene on, educated immune cells that are trained to see NY-ESO-1 can kill these cancer cells.
The researchers have decided to add a new drug, called nivolumab, to their vaccine/decitabine combination. They hope that by combining these strategies, they will be able to effectively educate the immune system of patients with MDS to see and kill their own cancer cells.
Testing of the blood and bone marrow over time for patients who get this combination will be conducted to ensure the approach is safe and to see how well it has done in educating the immune system.
Poor and minority children with asthma experience a disproportionate high percentage of asthma exacerbations, emergency department visits, hospitalizations and missed school days.
Traditional delivery models where care is received in physician offices and focused on acute care have limited success in improving outcomes in this population.
The researchers propose that a multifaceted intervention — that uses the Chronic Care Model as a framework to integrate the delivery of health services to children with asthma and from vulnerable populations — will reduce asthma morbidity and health inequities.
Components of the Chronic Care Model will be operationalized through:
Aligning with Schools To Help Manage Asthma (Project ASTHMA) will be delivered in the community at school-based health centers that are established health care systems and therefore can improve the sustainability and reproducibility of this intervention.
The chronic care model provides guidance for creating a comprehensive system change that integrates several interventions and is more likely to be successful than individual interventions. The researchers hypothesize that this multifaceted, health services intervention will decrease the frequency of asthma symptoms, asthma exacerbations, missed school days and improve lung function and quality of life.
Developing diagnostics that aid the discovery of stroke origin would represent a major advance in stroke workup.
The advent of endovascular thrombectomy devices has enabled the investigation of freshly retrieved thrombi after stroke treatment.
The researchers are proposing to develop biomarkers to characterize the origin of the stroke from characteristics of the blood clot.
Such biomarkers could be implemented at the point-of-care to reduce time and cost of post-stroke workups and could help determine the origin of cryptogenic strokes.
To do this, the researchers will collect resected clots from stroke thrombectomy treatments and use clot characteristics to develop predictive algorithms to classify stroke origin.
Combining analysis of clot histology, gene expression, medical imaging and patient medical information and outcomes, the researchers will characterize stroke cases with different known origins.
Significant differences between etiologies will be incorporated into a machine learning pipeline to develop computational algorithms to classify different types of stroke.
Results from this study will be the springboard for larger efforts in developing biomarkers to aid in the clinical workup of stroke.
The study is a multi-disciplinary effort to develop a novel antibody-based treatment for patients with acute myocardial infarction (MI).
Based on a growing body of evidence that excessive accumulation of inflammatory immune cells can impair cardiac repair after MI, the investigative team has developed a functionblocking monoclonal antibody (mAb) targeting E-selectin, an adhesion molecule that plays an important role in inflammatory cell mobilization and recruitment after cardiac injury.
The central purpose of the study is to complete preclinical studies in swine, while testing the hypothesis that administration of anti-E-selectin mAbs early after MI will improve post-infarction myocardial repair by reducing inflammatory cell infiltration in damaged heart muscle, thereby attenuating adverse cardiac remodeling and preventing the development of heart failure.
Ultimately, clinical translation of this new therapeutic strategy would significantly improve the treatment of millions of people who suffer from MI each year.
Patients with advanced chronic kidney disease (CKD) and end-stage renal disease on dialysis have an increased incidence and prevalence of cardiovascular diseases (CVD), with more than 50 percent of deaths attributed to cardiac causes.
Their gut bacterial composition is altered by the uremic milieu and by multiple dietary and therapeutic interventions. Altered gut bacterial composition then worsens the underlying metabolic imbalances and inflammation, leading to increased atherosclerosis and CVD risk.
Researchers have previously presented a novel finding of increased abundance of Prevotella Copri in patients undergoing peritoneal dialysis. These changes resulted in altered cholesterol metabolism pattern when introduced to mice.
Moreover, using National Health and Nutrition Examination Survey participants’ data, the researchers have shown that yogurt consumption (as a natural source of probiotics) is associated with decreased odds of developing proteinuric kidney disease, suggesting a benefit of restoring microbial symbiosis in CKD patients to inhibit disease progression and the risk of CVD.
The researchers will evaluate the mechanisms by which P. Copri abundance is altered in peritoneal dialysis patients, examine its effects on local inflammatory cell populations and mechanistically decipher how P. Copri affects cholesterol homeostasis.
Fewer than 10 percent of people diagnosed with pancreatic cancer live beyond five years. Most patients with pancreatic cancer are diagnosed in late stages when potentially curative surgery is no longer an option. Efforts to be able to detect pancreatic cancers in earlier stages are crucial to help decrease the number of people who die from pancreatic cancer.
It has long been known that genetic information specific to cancer cells can be detected in the blood of some cancer patients. Current technologies are enabling the identification of this cancer-specific genetic information directly from blood samples allowing for “liquid biopsies” that offer the potential of making cancer diagnoses directly from blood tests.
The development of new liquid biopsy technologies that can identify smaller amounts of genetic information more economically could potentially lead to blood tests that are able to detect smaller, more curable tumors and could be used for lung cancer screening.
The recent identification of CRISPR-Cas systems, bacterial immune systems adapted to recognize specific genetic sequences, that can accurately detect very small quantities of specific genetic sequences are an attractive platform to develop next generation liquid biopsy tests that are not only accurate, but also economical.
The pilot project’s goal is to develop a CRISPR-based blood test that can accurately and economically identify genetic sequences specific to pancreatic cancers in order to identify patients with early stage pancreatic cancer.
The researchers have developed a humanized mouse line to test the effect of inhibiting an enzyme, phosphodiesterase 4D (PDE4D), which is known to play a crucial role in the mediation of memory. Although dozens of compounds have been reported to functionally enhance memory in animal models, these drugs have not proven beneficial in improving cognitive performance in disorders affecting memory and cognition, such as Alzheimer’s disease or schizophrenia, in humans.
Despite the promise of new drugs which inhibit the actions of PDE4D, the challenge of identifying animal models that are predictive and translate well to the human condition remains. This collaborative project between UB and Tetra Discovery established a line that contains a primate-specific sequence which mimics the action of PDE4D in humans. The study involves a global, quantitative proteomics/systems-biology analysis to identify differences between the brains of humanized PDE4D mice and wild-type littermates following PDE4D inhibition.
Biomarkers of the effects of newly synthesized PDE4D inhibitor drugs will be evaluated as exploratory biomarkers in human phase 2 clinical studies. The outcomes of the project will accelerate the development of highly selective PDE4D inhibitors as novel treatments for illnesses that affect memory and cognitive functions.
If successful, the project will contribute to the reduction of health disparities in our community, a major goal of the CTSI’s Translational Pilot Studies Program. Alzheimer’s disease and schizophrenia affect millions of Americans, but they exhibit consistent and adverse disparities among blacks and Hispanics compared to non-Hispanic whites.
Oral mucositis, a painful and debilitating condition which causes ulcers in the mouths of chemotherapy and radiation patients, occurs in nearly all head-and-neck cancer patients. There are no preventative measures or treatment options at present that are completely effective.
Chronotherapy is a potential solution. Treatments are timed to coincide with stages of the circadian clock that is operative in every tissue of an organism, producing fewer side effects. Although chronotherapy has been shown to work in pre-clinical models, the unpredictable variety of circadian rhythms in the human population has prevented its application in clinical settings.
Researchers will conduct next-generation sequencing (RNAseq) to identify the genes associated with 24-hour patterns of radiosensitivity, and then coordinate treatments to each patient’s individual circadian cycle to reduce the severity of mucositis and improve the patient’s quality of life.
Expression for the genes will be assessed by saliva melatonin, monitoring rest and activity cycles, and morning-evening questionnaires, allowing for modification of the therapeutic schedule for each individual patient to the circadian phase associated with minimal side effects.