Bold Ideas Already Funded
Deciphering the Role of the Tumor Microenvironment in Primary and Metastatic Pancreatic Ductal Adenocarcinoma
This innovative project will leverage the opportunity to obtain matched primary and metastatic biopsies in pancreatic cancer patient for single cell sequencing and to derive organoid culture. This proposal will address how biological differences in the metastatic and primary tumor translate to different therapeutic niches within the same patient. Ultimately, results from this project will help to parse out the critical question of why patients with multifocal disease often have differing intertumoral responses to chemotherapy.
Next Generation Drug Discovery: Looking Beyond Canonical Drugs Using Mechanistic AI
Future treatments for complex diseases like cancer and drug resistant infections will likely involve a combination of multiple therapeutic modalities targeting neurological, immunological and metabolic processes. Yet we lack a rational basis to design such multimodal treatments. To address this, we will develop a novel workflow to discover multimodal therapies for drug-resistant infections using mechanistic AI methods.
Patient-Centered Pathology Communication Tools for Prostate Cancer Patients
The 21st Century Cures Act mandates immediate release of test results, including surgical pathology reports, to patients. Research shows that most patients do not understand their pathology report and nearly all are worried by the reports even when results are benign. Patient-centered pathology communication tools, such as the patient-centered pathology report, and pathology explanation clinics, may help bridge the communication gap between patients and the information contained in the pathology report. This project aims to evaluate the effectiveness of patient-centered pathology tools to improve diagnosis knowledge and preparation for treatment decision, while mitigating worry and confusion in prostate cancer patients. If found to be effective, these tools could be adapted and disseminated to support all patients receiving a surgical pathology diagnosis in the future.
Investigating Active Surveillance for Management of Low-Risk Basal Cell Carcinoma in the Elderly
Despite being the single most common cancer worldwide, basal cell carcinoma (BCC) has low morbidity, extremely low mortality, and – in the case of low-risk lesions – no clear benefit of treatment for many patients. We are performing a pilot randomized controlled trial to determine whether active surveillance (watching rather than treating) is a safe and acceptable alternative to standard treatment for low-risk BCC in patients aged 65 and older. Establishing active surveillance as a viable alternative for low-risk BCC can decrease unnecessary procedures, combat rising treatment costs, and promote distributive justice by improving access to dermatologists for other patients with greater need.
Tissue That Naturally Regenerates, Almost Every Time
Andrea Alford, Ph.D.
Jaimo Ahn, M.D., Ph.D.
Bone fractures are extremely common, but cellular mechanisms underlying successful, failed, or delayed healing are not known nor are they considered during an individual patient’s fracture care. Our bold idea is to connect attributes of stem and progenitor cells present in a fractured bone to healing outcomes of individual patients by establishing a prospective skeletal progenitor cell phenotyping program conducted in parallel with longitudinal clinical, patient-centric assessments of fracture healing. The resulting data sets derived from individual patients will inform diagnostic and interventional hypotheses aimed at personalizing bone fracture care.
Detection of Exhaled Breath Markers After Traumatic Brain Injury Using Point of Care Gas Chromatography
The innovation of our project is in its approach to develop a technology to give healthcare providers rapid diagnostic information that will assist with their evaluation of patients with acute traumatic brain injuries and to guide their management and treatment plans. This award by a Research Scout will enable the critical de-risking of our technology and make us more competitive for future federal funding and commercialization opportunities.
Novel Depression Target
Depression is a leading cause of disease burden and disability in the US with 1 in 8 women in the experiencing depression, almost twice the rate as men. Depression in women is often linked to decreases in circulating hormones, especially estradiol. Recent work has found that women diagnosed with a mood disorder have much higher levels of the estradiol metabolizing bacteria. This presents a novel, peripheral, target for treating depression in women.
Strengthening Preclinical Models of Infection with Ambient Temperature
Jean Nemzek, D.V.M., M.S., D.A.C.V.S.
Once considered the gold standard for sepsis studies, mouse models have become controversial due to decades of promising preclinical findings that have failed to translate into humans. We suggest these models do not recapitulate the human condition due to the inherent cold stress and immunocompromise experienced by mice housed under standard laboratory requirements. If our studies are successful, simply raising room temperature will produce a more relevant platform for preclinical studies and advance the development of effective biomarkers and therapeutic strategies for sepsis.
Kidney Organ Quality Education Initiative
The goals of our research project are 1) to develop and refine an education tool to support patient-centered decision making for kidney transplant candidates about acceptable donor organ quality based on individualized outcome estimates, and 2) collect feedback on the tool from patients and transplant providers. Despite ample national data and analytic frameworks, there is currently very little patient-centered education provided to patients on how variations in donor kidney quality may impact their own individual outcomes. Our educational innovation will meet an unfulfilled need, as it not only significantly enhances patient education but helps patients directly engage in decision making that can help achieve their optimal outcomes in a transparent fashion.
Cardiomyocyte Autonomous and Non-Autonomous Mechanism for Cardiac Repair
Ischemic heart disease, often caused by acute myocardial infarction (MI), is the leading cause of morbidity and mortality in the developed world with millions of patients developing heart failure due to myocardial scarring and ineffective tissue healing. Studying adult mammals that exhibit enhanced cardiac healing and the underlying cellular mechanisms regulating such a phenomenon has the potential to guide the development of novel clinical therapies. This project will focus on understanding the cardiomyocyte metabolic adaptations that occur during and after MI in spiny mice in an attempt to develop novel therapeutic strategies to improve cardiac function and reduce heart failure.
Dynamic Scheduling for Otolaryngology Using Machine Learning Models
This project seeks to develop and implement into clinical practice an intelligent triaging model for patients with dizziness and vertigo using machine-learning. The project will include validation that the augmented human intelligence triage system will increase accuracy of necessary appointments, improve access for surgery, decreases costs, and improve post-treatment clinical outcomes. The learnings and structure will be used in the future for other clinical areas of otolaryngology.
Deployment of Wearable Technologies and Ecological Momentary Assessment to Develop a Multimodal Digital and Clinical Database for Personalized Prediction of Fatigue, Pain, and Cognitive Disturbance Trajectories
Although treatments for multiple sclerosis (MS) have successfully evolved to markedly reduce neurological disability, problematic fatigue, cognitive dysfunction, and pain persist and severely impact the quality of life of persons with MS (PwMS). The failure to develop effective interventions for these symptoms is related to our inability to capture their dynamic nature that demonstrates significant variability across and within days as well as difficulty concomitantly measuring the critical inputs of sleep and circadian rhythms (our body’s internal clock). Therefore, we will use mobile application deployed ecological momentary assessment and wearable data to comprehensively phenotype symptoms, sleep, and circadian phase longitudinally to inform the design of patient specific interventions.
Ultra-High-Speed Imaging for Advancing Ultrasound-Based Theranostics
This research idea integrates two cutting-edge microscopy techniques, ultra-high-speed microscopy and confocal microscopy in real-time, to push the boundaries of current knowledge on both physics and biology aspects of acoustic droplet vaporization. The findings will provide a mechanistic understanding of this phenomenon, which is incredibly understudied, and expand its potential biomedical applications.
Diversification of Cortical Function in Health and Disease Via Developmentally Programmed Deletions in Large, Brain-Specific Genes
Mental disorders of poorly understood etiology are having increasingly large impacts on human populations, including schizophrenia and autism. Wilson and colleagues are developing genomic tools to ask whether a specific type of gene mutation occurs during neurodevelopment to create purposeful genetic heterogeneity of brain cells. These mutations would diversify brain neural networks in normal individuals, whereas developmental stresses in utero might create too many mutations, leading to mental disorders. If validated, this model could change our understanding of how mental health might be influenced by interventions in pregnancy.
Towards A Fundamental, Operative Law of Mammalian Cerebral Cortex Function
Compared to other mammals, humans have a massively expanded neocortex that supports our unique capacity for language, abstract thought, and higher-order cognition. Despite this importance, we still know very little about what the neocortex does to control our behavior, let alone how these functions arise. This project will employ cutting edge tools to test the hypothesis that the neo-cortex instructs synaptic plasticity in evolutionarily ancient sub-cortical structures, thereby consolidating learned information at the earliest stages of the central nervous system.
Screening FDA Approved Therapies in a Brain Organoid Model of Neural Tube Defects: Unveiling Risk Factors and Potential Treatments
Neural tube defects (NTDs) are serious developmental abnormalities in the early nervous system, leading to disability, paralysis, or even neonatal mortality. Factors such as genetics, nutrient deficiencies, and certain medications contribute to the risk of NTDs. Our objective is to investigate the impact of an FDA-approved drug panel on a brain organoid model of NTDs, aiming to uncover new pharmaceutical teratogens and potential preventative treatments.
Neurotransmitter Switching: An Epilepsy Pathomechanism Hiding in Plain Sight?
Neurotransmitters are chemicals that transfer information between cells in the brain and as such fundamentally determine the way the brain works. Recent evidence suggests that individual neurons within the adult brain can switch expression from one neurotransmitter to another, but it is not yet clear to what extent this process occurs in neurologic disease. We will test whether seizures trigger “neurotransmitter switching”, a finding that would provide a new explanation for how the brain is altered in epilepsy.
The Impact of Baseline Knowledge and Patient-Related Factors on the Receipt of Surgical Care Among Black Patients With Carpal Tunnel Syndrome
Our study examines the intersection of patient knowledge, prior experiences with the healthcare system and provider characteristics that impact the willingness to undergo treatment for carpal tunnel syndrome among Black patients. We will assess patient preferences for adjunctive educational content during a surgical consultation, specifically the role of racially-concordant visual representations of hand conditions and treatments among Black patients. We anticipate that increased understanding of the burden of disparities and inequities that our Black patients experience when seeking care for hand conditions will facilitate patient-centered changes in our approach, deconstruction of barriers to hand surgery care, and a decrease in the reluctance and distrust of the healthcare system among Black patients impacted by these conditions.
Dramatic Reduction in Sequencing Cost for Transcriptomic Profiling of Rare Cells in Single-Cell/Single-Nucleus RNA-Seq Experiments Through Targeted Sequence Enrichment
Single-cell/single-nucleus RNA-seq technology presents unprecedented opportunities to study the transcriptomes of rare cells (< 1%) in complex tissues, but high sequencing cost remains a significant obstacle for wide adoption, as transcriptomes of the rare cells cannot be obtained without sequencing the whole single-cell-barcoded library. We aim to develop a targeted sequence enrichment approach designed to isolate all the DNA molecules originated from transcripts of the targeted rare cells in an unbiased manner from the single-cell-barcoded sequencing library, therefore achieving high coverage of the targeted transcriptomes with minimal sequencing requirements. Successful implementation of this approach downstream of standard single-cell library creation procedures would enable transcriptomic exploration for rare cells at the single-cell resolution at a cost-to-coverage ratio approaching conventional bulk RNA-seq.
Gene-Editing Therapeutics for Hereditary Eye Diseases
Shahzad Mian, M.D.
Lev Prasov, M.D., Ph.D.
Yan Zhang, Ph.D.
Gene-editing therapy promises a permanent cure for ocular defects and blindness by tackling the genetic root cause of hereditary eye conditions. This translational research project will develop therapeutic and delivery strategies for correcting genetic mutations in the common hereditary corneal dystrophies using cutting-edge CRISPR technology. A successful implementation and effective translation into clinical practice will offer a blueprint for addressing many other genetic disorders affecting tens of millions of people worldwide.
An Antibody-Based, Targeted, Nanoparticle Drug Delivery System for Inflammatory Disease of the Airway
Chronic rhinosinusitis (CRS) is a severe inflammatory disorder of the upper airway sinonasal mucosa that affects up to 12% of the United States population and substantially diminishes the quality of life and productivity of patients. Up to 20% of patients remain unresponsive to current medical treatment, necessitating 600,000 sinus surgeries annually. We aim to develop a novel, antibody-based, synthetic protein nanoparticle drug delivery system that can incorporate anti-inflammatory medication for safe and effective local treatment of sinonasal inflammation. The far-reaching benefits of a targeted, anti-inflammatory drug delivery system will extend beyond CRS to other chronic inflammatory diseases.
Quantitative Imaging Biomarker to Predict Lung Metastasis
We propose a novel, clinically translatable imaging method to predict patients at high risk for lung metastases, which would fill a massive void in cancer research and clinical care. We propose to accomplish this transformative objective by imaging pathophysiologic changes that occur in the lungs before development of metastases detected by conventional anatomic imaging. If successful, this imaging method could become a prognostic biomarker that helps oncologists tailor therapy for individual patients based on risk for metastasis.
Identifying Novel Therapies for Sickle Cell Disease
Sickle cell disease (SCD) is a devastating blood disorder characterized by repeated pain crises, chronic organ dysfunction, and reduced life expectancy. SCD affects primarily individuals of African descent and has unfortunately been historically under-funded compared to other equally prevalent disorders. We aim to identify novel therapies for SCD using a high-throughput screen that aims to test thousands of small molecules (a large proportion of which are uniquely available at the University of Michigan) for their ability to ameliorate the disease. This project is bold, highly promising, can only be done at an institution like the University of Michigan, and has the potential to result in meaningful improvements in the lives of hundreds of thousands of individuals affected with this disease.
Computational Modeling of Cell-Paired Morphological and Gene Expression Data
We want to develop and combine two new technologies: (1) experimental approaches for measuring both morphology and gene expression in the same single cells and (2) computational models that link the two measurement types. We hope to develop general tools that will yield insights into the relationship between gene expression and morphology across many cell types, cellular perturbations, and diseases.