Project Title: Efficacy and Selectivity of a Novel Drug Combination in Aggressive Lymphoma
Mentor: David Fruman, MD
The objective is to evaluate the efficacy and tolerability of ABT-199 in combination with HMGCR inhibitors (statins) in preclinical models. ABT-199 is a small molecule inhibitor of BCL-2, a key pro-survival protein that is highly expressed in many leukemias and lymphomas. There is an urgent need for new therapeutic approaches in patients with relapsed/refractory DLBCL. Here we propose to evaluate a novel approach with potential for immediate clinical translation, by combining ABT-199 with FDA-approved drugs (statins) whose safety profile is very well established. To date there have not been any studies aimed at evaluating the efficacy of combining statins with BCL-2 antagonists in any context. While our preliminary data identify marked synergy between these inhibitors in human cell lines and primary mouse lymphoma cells, whether statins plus ABT- 199 maintain synergy in vivo will be critical to supporting future clinical trials. Although both ABT-199 and statins have extremely favorable tolerability profiles at anti-leukemic doses,6-10 it will also be important to test whether the combination maintains selectivity for lymphoma cells versus normal hematopoietic cells. AIM 1. Evaluate efficacy of statins + ABT-199 in a syngeneic, immune-competent mouse model of double-hit B cell lymphoma. A collaborator has established a mouse lymphoma model driven by BCL-2 and MYC that can be studied in vitro and in vivo. We will transplant one lymphoma line into syngeneic mice and determine the optimal statin to treat with using Rap1a in tumor tissue as a marker of pharmacodynamics response. Subsequently, a second cohort of mice will be treated with single or combined agents after disease is established. We will monitor the survival of the mice and determine tumor burden in lymphoid organs. AIM 2. Assess the selectivity of statins + ABT-199 for lymphoma versus normal hematopoietic cells. It is important to preserve immune function in lymphoma patients, particularly in this era of expanding immunotherapy. ABT-199 is known to deplete normal B cells but is less toxic towards T cells. Here we will test whether hematopoietic stem cells, T cells, and NK cells can be spared in vitro and in vivo, when treated with simvastatin + ABT-199 at concentrations that kill lymphoma cells.
Project Title: "Audiological Evaluation of Speech-in-Noise Perception in Impaired, Aged EarsThrough Measurement of Central Auditory Processing of Complex Sounds"
Mentor: Fan Gang Zeng, MD
My doctoral research concerns how cochlear deficits versus neural deficits effect central auditory processing. Cochlear implant users have impaired cochlear function, which in part degrades speech perception in background noise. Conversely, patients with central auditory processing disorders have normal cochlear function yet struggle to understand speech in noise. The first part of my research investigates central auditory processing of spectro-temporal cues in cochlear implant users to determine how electric sounds integrate for speech intelligibility. The second part of my program investigates the effect of activating “attention-mediating” receptors (nicotinic acetylcholine receptors) in the brain on auditory perception. The latter work will address whether oral nicotine enhances auditory attention in individuals with auditory processing deficits (e.g., dyslexia, ADHD).
Project Title: Structure-function mechanism of oncogenic p53 mutant reactivation by thiosemicarbazones
Menotr: Hudel Luecke PhD
The tumor suppressor p53 is an important cell-cycle regulating transcription factor that is mutated in 50% of human cancers. Most of these oncogenic p53 mutations create a single amino acid substitution in the DNA-binding domain (DBD), leading to continued expression of full-length but nonfunctional p53 protein. The most common of these p53 mutations, R175H, causes the DBD to become thermodynamically destabilized, losing its DNA-binding activity, and becoming nonfunctional at physiological temperatures. A pharmaceutical that can restore wild-type p53 function to R175H, or any of these single amino acid mutants, could have an enormous impact on our ability to treat cancers with p53 mutations. We identified a class of small molecules, copper thiosemicarbazones, which are able to stabilize the R175H DBD and G245S DBD (another oncogenic mutation) in vitro and induce p53R175H- and p53G245S-dependent cell death in cancer cells, suggesting that these small molecules have the potential to target many oncogenic p53 mutants for reactivation. The objective is to understand the molecular mechanism that allows copper thiosemicarbazones to restore function to oncogenic p53 mutants, from atomic-level interactions with the p53 DBD to the changes in the biochemical functions of the p53 DBD. Our aims: 1) Understand the characteristics of copper thiosemicarbazone binding and stabilization of oncogenic p53 DBD. 2) Determine interactions of copper thiosemicarbazones with oncogenic p53 DBD and structural effects upon binding. 3) Evaluate effects of copper thiosemicarbazone on the DNA-binding of oncogenic p53 DBD. 4) Evaluate effects of copper thiosemicarbazones on oncogenic p53 DBD protein-protein interactions.
Project Title: EEG studies of the human brain motor system -- New insights into learning and plasticity
Menotr: Steve Cramer, MD
Stroke is the leading cause of long-term disability among adults in the United States, with >50% of stroke survivors demonstrating persistent motor impairments. Increased plasticity after stroke can help reduce long-term disability. As with normal development, there are critical periods in post-stroke plasticity. Rat models of stroke characterize a critical period in which initiating enriched rehabilitative training leads to improved recovery. Despite potentially significant implications for optimizing rehabilitation, there are very limited data on critical periods of plasticity after stroke in humans. However, behavioral and neuroimaging markers of neuroplasticity in the period after ischemic insult may help to characterize a similar critical period in stroke patients.
The overarching goal of this project is to study changes in motor system plasticity in the weeks following a new ischemic stroke. Specifically, the proposed project examines neuroplasticity in the context of motor learning, a model which provides a useful framework for understanding post-stroke recovery. A total of 54 subjects with new ischemic stroke will be studied with behavioral testing and dEEG at one of 3 time points: 4-8 days, 14-20 days, or 40- 60 days post-stroke. The specific aims of the fellowship proposal have direct implications for optimizing rehabilitation effects and improving stroke recovery.
Specific Aims: Aim1 will test the hypothesis that motor skill acquisition over a period of short-term motor training and retention of training will decline with time after ischemic stroke. Aim 2 will test the hypothesis that degree of resting-state coherence will correlate with degree of motor skill acquisition and retention, and as such coherence will decrease with time after ischemic stroke.
The present methods for assessing the effect that ischemic injury has on motor network function are limited. The proposed studies will be performed using dEEG, a technique with good spatial resolution and excellent temporal resolution that can be readily employed in wide ranging clinical stroke settings. In addition to providing support for these specific studies, the experiences supported by the TL-1 Scholars Training Program will provide me with the highest caliber training in human neuroscience research and neuroimaging in preparation for a career of translational research in stroke rehabilitation.
Project Title: Affective Response to Exercise, Affective Style, Perceived Competence, and Physical Activity Behavior in Adolescent
Menotr: Margaret Schneider PhD
The proposed study will test whether adolescents’ affective style predicts their physical activity (PA) behavior. Further, it will determine whether enjoyment of exercise mediates the potential relationship between affective style and PA behavior. Epidemiological evidence shows that there is a precipitous decline in PA during adolescence and, by age 15, most do not meet the USDHHS standards. Unfortunately, previous interventions for PA promotion have been inefficient, especially in relation to cost. Therefore, novel approaches to promote PA behavior in adolescents are warranted.
One promising factor that may play an important role in PA promotion is an individual’s affective response to exercise. Enjoyment of exercise has been shown to predict PA behavior in both adults and adolescents. Further, interventions that targeted enjoyment of PA have been successful at increasing PA levels in adolescents, especially in high risk, reluctant exercisers (individuals who do not enjoy exercise). Affective style is the predisposition of an individual to respond either positively or negatively to emotion-eliciting stimuli. Reluctant exercisers may be predisposed by their affective styles to enjoy exercise, which may in turn predict whether they engage in PA behavior. The present study tests the hypothesis that adolescents with a positive affective style will engage in greater PA compared to those with negative affective style. Further, we hypothesize that enjoyment of PA will mediate the relationship between affective style and PA behavior. These hypotheses will be tested by addressing the following two aims: Aim 1. Determine whether adolescents’ affective style is associated with their PA behavior. The outcome variable, PA behavior, will be defined as a) self-selected exercise intensity, b) exercise intensity in a physical education (PE) class, and c) time spent in MVPA per day, averaged across a week of ambulatory monitoring by accelerometer. Hypothesis will be tested separately for each outcome variable. Aim 2. Determine whether enjoyment of exercise mediates the association between affective style and PA behavior. Enjoyment of exercise will be operationalized as the affective response to a standardized lab-based exercise task.
Project Title: The use of Diffuse Optical Spectroscopy in the diagnosis of vascular and adipose tissue dysfunction
Menotrs: Pietor Galassetti MD, PhD and Bruce Tromberg PhD
Goutham proposes to adapt Diffuse Optical Spectroscopy (DOS), a novel methodology developed at the Beckman Laser Institute, to study metabolic and vascular disease. DOS offers an innovative quantitative approach to near-infrared spectroscopy, providing substantially more comprehensive information concerning tissue blood flow, oxygenation and energy substrate utilization, which can lead to better prevention, diagnosis and monitoring of onset and progression of vascular impairment in dysmetabolic conditions, especially during the earliest subclinical stages, which are particularly difficult to identify. Importantly, research results offer the potential of rapid translation into clinically applicable methodologies and new devices. In Specific Aim he we will compare, in adults with both healthy and impaired vascular systems, the assessment of endothelial function by DOS with the current “gold-standard”, flow-mediated dilation by brachial artery ultrasound. We hypothesize that DOS will accurately reproduce ultrasound results, while providing more comprehensive metabolic information. In Specific Aim II the DOS will be used to assess tissue oxygenation in subcutaneous adipose tissue. With growing evidence indicating the crucial role of adipose tissue dysfunction in metabolic disease, the non-invasive study of adipose tissue may become a useful tool yielding critical insights into global metabolic function. To this end, he will perform static multi-channel DOS measurements on a variety of adipose tissue sites in healthy, obese and diabetic subjects, under the hypothesis that the magnitude of adipose oxygenation impairment, reflected by altered broadband spectral signatures, will correlate with the degree of insulin resistance and/or other key metabolic variables.
Project Title: Identifying the source of resistance to excitotoxic cell death in a mouse strain that is otherwise highly vulnerable
Menotr: Oswald Steward PhD
The cause of the selective neurodegeneration in Huntington’s disease (HD) has not yet been fully elucidated, but there is strong evidence to suggest that excitotoxicity play a role. Vulnerability to excitotoxic cell death varies dramatically across strains of mice and is genetically determined, which makes these models very useful for studying the control of vulnerability and resistance to excitotoxicity. To explore the role of strain background in mouse models of Huntington’s disease, mice with an HD mutation were backcrossed 10 generations to a mouse stain that is inherently vulnerable to excitotoxic neurodegeneration (FVB/N). Remarkably, this vulnerable mouse strain developed essentially complete resistance with age when carrying one or two copies of the HD mutation compared to wild type littermates. These results imply one of two things: the FVB/N strain possesses the critical effector gene responsible for conferring protection against excitotoxicity but that its effects are not induced unless the neuron has expression of mutant huntingtin protein. Alternatively, the genes responsible for conferring protection are derived from the original “resistant” mouse strain (before backcrossing) and are linked to the locus of the HD mutation. Here, we focus on two experimental objectives: to characterize induced resistance to excitotoxic cell death, and to identify genes that are differentially expressed in mice that develop resistance to excitotoxic cell death. The preliminary evidence that there are genes, or changes in gene expression, that can confer protection against neurodegeneration leads us to pursue molecular mechanisms that can be targeted for therapeutic intervention.
Project Title: Real-time Laser Speckle Imaging as a Diagnostic Tool in the Treatment of Port Wine Stain Through Image-guided Laser Surgery
Menotrs: Bernard Choi PhD, J. Stuart Nelson MD PhD, and Kristen Kelly MD
Port Wine Stain (PWS) birthmarks are vascular malformations seen in ~12,000 births a year. While the obvious cosmetic detriments can have profound effect on an individual’s psychosocial development, facial PWS lesions have also been linked to a higher propensity for glaucoma and seizures, thereby compounding the need for a cure. Currently the data collected with this research has shown that Laser Speckle Imaging (LSI) improves the treatment success through the development of real-time image guided laser surgery. This proposal further develops LSI as a diagnostic tool by enabling real-time processing combined with concurrent clinical testing. Patient diversity has made certain comparisons difficult. The application of a Graphics Processing Unit (GPU) can be extended to medical imaging with the use of C programming interfaces, thus representing our design focus. Clinical Application LSI will be used in the operating room to assist surgeons in quantifying the amount of photocoagulation and hence reductions in blood flow. The utility of real-time LSI will be quantified by having two groups of patients: the control group with no LSI feedback, and the experimental group attaining feedback from real-time LSI images. Success of the treatment will be based on color images which will quantify the severity of PWS using an erythema index and will ultimately demonstrate the efficacy of our system.
Project Title: The Interpersonal Stressors of Pediatric Cancer Care: A Transdisciplinary Focus on Patients, Families and Healthcare Providers
Menotrs: Roxane Cohen Silver PhD
Cancer survivors face a potentially long illness experience marked by continuous waves of uncertainty and frequent stressors. Uncontrollable cancer care-related stressors may have serious psychological and physical health consequences. An important goal of translational research is to examine how the cancer experience affects the lives of these individuals in order to prevent or minimize potentially negative health sequelae. An initial step toward this goal is to identify the most prominent stressors in the cancer care trajectory and to recognize that they exist in a complex, interactive system with multiple contributing components. Ms. Juth is investigating this social system. Specifically, a three-phase program of research will examine how young cancer patients and their caregivers contribute to each other’s cancer experience. In Phase 1, the dyadic, interaction of adolescent and young adult patients and their primary caregivers in the family unit are examined. Phase 2 will explore the dyadic interactions between a more inclusive range of pediatric patients (age 8-21), their parents and their physicians in the healthcare setting. Phase 3 will utilize the findings from Phases 1 and 2 to develop and evaluate the efficacy of an intervention for healthcare providers of pediatric cancer patients. The first phase of data collection has begun along with the analysis of the data. Several presentations have been given and a number of manuscripts are also being prepared for submission.