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2017 ICTS PILOT AWARD RECIPIENTS

Kelly Biegler, PhD »

Mi Vida, Mi Salud: A novel mobile health intervention for the development of personal rules promoting weight loss, symptom management, and reduction in proinflammatory biomarkers in Latina breast cancer survivors

Abstract

Breast cancer and its treatment are associated with a range of symptoms (e.g., fatigue, pain, sleep disturbance, distress), which can persist years into survivorship and have a lasting negative impact on quality of life. Women with breast cancer are also at high risk for weight gain and developing comorbid chronic conditions such as obesity. Chronic inflammation may be a common mechanism associated with many breast cancer-related symptoms (e.g., fatigue and pain) and obesity. Lifestyle changes to reduce obesity and obesity-related inflammation have been shown to reduce symptom burden in this population. Lifestyle interventions delivered via mobile applications are on the rise in order to provide low cost, personalized options that capitalize on efforts to promote self-management and health behavior change. Self-management strategies (e.g., healthy diet and exercise), as part of a lifestyle intervention, have been associated with improved outcomes in cancer populations; however, these programs rarely included personalization to patients’ preferences, and have had limited success in demonstrating long-term adoption of health behaviors. Although a vast array of health and cancer-related smartphone applications exist, very few have undergone rigorous empirical investigation. We have developed Mi Vida, Mi Salud, a highly innovative M-health weight loss intervention that surpasses self-monitoring of health behaviors, as it provides personalized feedback about the relationship between symptoms, mood states, and health behaviors, prompting the patient to self-discover 1) individual stressors and triggers of poor health behaviors and symptom onset and severity and 2) preferential healthy behaviors and adaptive coping strategies to prevent or alleviate symptoms. While existing M-health interventions purport to provide ‘individualized feedback,’ Mi Vida, Mi Salud is the first M-health intervention to utilize an advanced, adaptive algorithmic technology that allows participants to self-discover personal rules of health behavior: health behaviors that have been identified and tailored to an individual’s beliefs and preferences, fortifying and reinforcing an individual’s motivation for health behavior change. Thus, we propose to build upon and extend our currently funded M-health weight loss study, Mi Vida, Mi Salud, to explore the effects of weight loss and symptom reduction on circulating proinflammatory biomarkers in Latina breast cancer survivors. Thus, the Specific Aim for the ICTS Pilot Award is to determine whether the provision of the Mi Vida, Mi Salud M-health intervention can decrease circulating proinflammatory cytokines (IL-1 and IL-6) at 3 months post-baseline (T2) compared to smartphone-based health behavior monitoring alone.

Daniela Bota, MD, PhD »

Preclinical Development of Coumarinic Compounds as a Novel, Mitochondrial-Targeted Therapy for Glioblastoma

Abstract

The goal of this project is to accelerate the preclinical development of a new drug for the most common and universally fatal brain tumors - malignant gliomas.

Malignant gliomas are highly hypoxic tumors, and the cells from the poorly oxygenated areas of the tumor have increased resistance to treatment. Our in press data (Oncotarget) suggest that mitochondrial adaptation of glioma cells to hypoxia is controlled by the mitochondrial protease and DNA-binding factor Lon. In vitro, Lon over-expression is associated with glioma resistance to the two most common treatment modalities: radiation and chemotherapy with temozolomide. In vivo, Lon over-expression causes accelerated tumor growth and shortens survival. Lon down-regulation using siRNAs decreases glioma cell proliferation, migration and survival in hypoxic conditions, but siRNA use is impractical in clinical setting. Through collaboration with another UCI faculty (Dr. Chris Vanderwal), we now have a specific, small molecule Lon inhibitor (coumarinic compound 4-CC4). CC4 is very effective in our glioma cell cultures, and has a synergistic activity with the standard of care therapies such as temozolomide. Furthermore, the coumarinic molecules are small, and have the ability to cross the blood-brain barrier. There are a number of coumarinic compounds already in clinical use.

Aimee Edinger, PhD »

Evaluation of sphingolipid-inspired small molecules as calorie restriction mimetics

Abstract

Obesity has reached epidemic proportions. According to the NIDDK website, 2/3 of adults and 1/3 of children ages 6-19 in the United States are overweight or obese. These rates are even higher in Hispanic and black populations. Given that obesity-related type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease cause significant morbidity and mortality, there is great interest in developing novel obesity treatments, including small molecule therapeutics.1-4 Nonetheless, few anti-obesity drugs are FDA-approved and existing agents are generally not very effective. Furthermore, the pipeline does not contain any apparent “homerun” products. Most existing therapeutics are designed to directly modulate hormone levels and/or signaling pathways associated with obesity. A limited number interfere with intestinal absorption (e.g. orlistat, lipase inhibitor that blocks fat absorption) or increase nutrient loss (e.g. SGLT2 inhibitors, inhibit glucose reabsorption from urine). Here, we propose an entirely novel strategy for combating obesity: putting cells, rather than the patient, on a diet.

This proposal will test the innovative idea that cellular starvation can phenocopy the effects of organismal starvation. The outcome of these experiments has very significant implications for both patients with obesity and the host of diseases that are mitigated by calorie restriction. We have already shown that 893 is safe when given long term, at least in mice, suggesting that 893 could be applied to chronic diseases such as obesity, not just cancer.

Angela Fleishman, MD, PhD »

SMAC mimetics as a therapeutic approach in myeloproliferative neoplasm

Abstract

Neoplastic cells evade death by upregulating anti-apoptotic proteins such as Inhibitor of Apoptosis Proteins (IAPs). SMAC mimetics are a drug class that bind IAPs causing their degradation and are actively being investigated in cancer clinical trials. The addition of tumor necrosis factor-alpha (TNF) is required for SMAC mimetics to induce death in normal cells. However, JAK2V617F mutant myeloproliferative neoplasm (MPN) cells are sensitive to SMAC mimetics alone. Therefore, we hypothesize that combining the SMAC mimetic LCL-161 with an anti-TNF agent will target the JAK2V617F-mutant cells in MPN while preserving normal cells. We will test this hypothesis using primary human MPN peripheral blood cells as well as MPN mouse models. These data will provide the rationale for the design of an investigator initiated trial testing LCL-161 in combination with a TNF blocking agent in MPN patients.

Felicia Lane, MD »

Determination of LOXL1 and Fibulin 5 levels in the vaginal secretions of women with and without pelvic organ prolapse

Abstract

Pelvic Organ Prolapse (POP) defined descent of the vaginal walls, apex of the vagina, or uterus is a potentially devastating condition that affects up to 50% of women with a lifetime risk of 20% to undergo a reconstructive procedure. The etiology has not been fully elucidated, but it is believed to be multifactorial in origin with vaginal childbirth and aging cited as major risk factors. Recently investigators have focused on the role of elastin in the development of POP. Lysyl oxidase--‐like 1 (LOXL1) and Fibulin--‐5 are crucial in the assembly and remodeling of elastin fibers. LOXL1 is a copper--‐dependent amine oxidase that functions to cross link tropoelastin monomers to create elastin polymers and Fibulin--‐5 helps to transfer elastin aggregates to microfibrils. Animal models lacking the Fibulin--‐5 gene developed POP spontaneously while those lacking LOXL1 developed POP 1--‐2 days postpartum. These findings have prompted investigators to evaluate LOXL1 and Fibulin--‐5 levels in human subjects but the results thus far have been heterogeneous as different biopsy sites have been used. The invasive nature of obtaining biopsy specimens has also limited the sample size of previous studies. We propose a translational feasibility study to determine if LOXL1 and Fibulin--‐5 can be extracted noninvasively from vaginal secretions. We will then compare the levels of these two proteins in patients with and without POP. Finally, we would like to correlate the levels of these biomarkers found in the vaginal secretions with those obtained from a vaginal biopsy. The overall aim of this project is to create a noninvasive standard for the measurement LOXL1 and Fibulin--‐5, which would lay the foundation for our ultimate goal of developing a screening test for POP.

Jeremiah Tao, MD »

A Digital Prosthetic Eye with Functional Eye Mimicry

Abstract

Current ocular prosthetics incorporate a static eye image onto an acrylic or glass shell. Insufficient prosthetic rotation combined with a lack of pupillary responses leads to negative body image among users.  We hypothesize that digital microscreen technology can be utilized for more realistic ocular prosthetics. Our recent proof of concept project used a video camera with facial detection software to capture and produce an image of a healthy eye.  Here was design, create, and test a secondary prototype of a digital prosthetic eye (DPE) featuring a microscreen with real time display of the conjugate movements captured by a microcamera.

Armando Villalta, PhD »

Regulatory T cell responses in muscle degenerative disorders

Abstract

Muscular dystrophy and idiopathic inflammatory myopathy include a group of disorders characterized by muscle
degeneration and chronic inflammation. Therapy for these disorders largely relies on glucocorticoids that broadly
suppress inflammation, but provide only a short delay in disease progression with many adverse side effects. Moreover,
the generalized suppression of inflammation by glucocorticoids may silence protective immune cell populations that are
anti-inflammatory and critical orchestrators of muscle regeneration. Thus, it is imperative to delineate the mechanisms
that regulate muscle degenerative versus regenerative inflammation, in order to design novel therapies that specifically
inhibit pro-injurious inflammatory responses. Recent studies using mouse models of acute muscle injury and Duchenne
muscular dystrophy (DMD) have shown that Tregs promote regeneration and inhibit a type 1, pro-inflammatory response
in muscle. However, the mechanisms by which Tregs modulate muscle inflammation and promote regeneration are not
well defined. This gap in knowledge hampers the clinical translation of animal studies, showing that Tregs promote
regeneration, and reduce the severity of muscular dystrophy. Furthermore, the lack of a detailed characterization of
Tregs in patients with DMD or other muscle diseases makes it difficult to ascertain the therapeutic potential of targeting
Tregs in these patients.

Mark Warschauer, PhD »

Telepresence robots for virtual academic inclusion and improved well-being, health, and social outcomes for homebound pediatric patients

Abstract

Due to increased survival rates, and reclassification of illnesses once considered fatal, there is a
growing population of children who are homebound due to chronic illnesses. This project aims to
address the lag between the scientific discoveries that have led to increased survival and needed
changes in the treatments and practices afforded to these children for quality of life. Recent
technological innovations, such as telepresence robots, (Figure 1) may allow for partnerships
between the technology, healthcare, and education fields to improve well-being, health, and
social outcomes for homebound pediatric patients. These robots allow for real-time, two-way
communication and have features that allow for integration of homebound pediatric patients in
existing school settings and peer social structures. The goal of robot use is for the patient to
engage in social and academic experiences in such a way that they contribute to healthy social
emotional development. These social experiences may also contribute to increased adherence to
prescribed medial regimens resulting in improved well-being and health outcomes for this
population. This project will provide an interdisciplinary partnership between schools of
Education, Informatics, and Pediatrics that will provide formal, objective research studies in
order to provide recommendations for use of the robots as supported by the psychology,
educational, and health care research literatures.

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