Citations

Abstract In this presentation, Dr. Griffin will describe the Technology-Enhanced Transitional Palliative Care (TPC) study, a randomized controlled trial testing the efficacy and cost-effectiveness of an intervention to address FCGs’ unmet needs in order to improve their health and well-being. Nurse interventionists use video visits to teach, guide and counsel FCGs in rural areas caring for someone receiving palliative care and transitioning form hospital to home. In addition to providing background on the importance of addressing unmet family caregiver needs during care transitions for patients receiving palliative care, she will describe the study design, sample, intervention and control group procedures, including the use of video visits, and outcomes assessed. This presentation will provide necessary context for the remaining presentations.

Background/Objectives: CSCs are critical drivers of the tumor and stem cell phenotypes of glioblastoma (GBM) cells. Chromatin modifications play a fundamental role in driving a GBM CSC phenotype. The goal of this study is to further our understanding of how stem cell-driving events control changes in chromatin architecture that contribute to the tumor-propagating phenotype of GBM. Methods: We utilized computational analyses to identify a subset of clinically relevant genes that were predicted to be repressed in a Polycomb repressive complex 2 (PRC2)-dependent manner in GBM upon induction of stem cell-driving events. These associations were validated in patient-derived GBM neurosphere models using state-of-the-art molecular techniques to express, silence, and measure microRNA (miRNA) and gene expression changes. Advanced Poly(β-amino ester) nanoparticle formulations (PBAEs) were used to deliver miRNAs in vivo to orthotopic human GBM tumor models. Results: We show that glioma stem cell (GSC) formation and tumor propagation involve the crosstalk between multiple epigenetic mechanisms, resulting in the repression of the miRNAs that regulate PRC2 function and histone H3 lysine 27 tri-methylation (H3K27me3). We also identified miR-217-5p as an EZH2 regulator repressed in GSCs and showed that miR-217-5p reconstitution using advanced nanoparticle formulations re-activates the PRC2-repressed genes, inhibits GSC formation, impairs tumor growth, and enhances the effects of ionizing radiation in an orthotopic model of GBM. Conclusions: These findings suggest that inhibiting PRC2 function by targeting EZH2 with miR-217-5p advanced nanoparticle formulations could have a therapeutic benefit in GBM.

Cardiac amyloidosis (CA) is a progressive condition resulting from the deposition of amyloid fibrils in the heart, which leads to severe diastolic dysfunction and restrictive cardiomyopathy. The disease has two main subtypes: light-chain and transthyretin (TTR) CA, with the latter subdivided into wild-type and hereditary forms. Despite advances in diagnostic imaging, early detection remains a challenge due to non-specific symptoms that mimic other cardiac conditions. Treatment has evolved significantly with targeted therapies like TTR stabilizers, gene silencers, and RNA interference, showing promise in altering disease progression. However, barriers such as high costs, limited availability of genetic testing, and inadequate multidisciplinary care continue to impede comprehensive management. Future strategies should focus on integrating novel gene-editing therapies, expanding access to diagnostics, and enhancing multidisciplinary care models to improve outcomes. Overall, early diagnosis, equitable access to therapies, and personalized management plans are crucial to advancing care for CA patients.

Abstract Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the senescence-associated secretory phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Senescence is a complex and highly heterogenous phenotype and despite tremendous progress in recent years we are still far from fully understanding it. There is no single, stand-alone marker that allows the identification of senescent cells, posing a challenge to their identification and targeting. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. In my talk, I will first describe some of our recent efforts to accurately map senescent cells in different tissues, including the application of imaging methods involving artificial intelligence. Additionally, I will describe how mitochondria contribute to the development of senescence and resistance to cell-death. Finally, I will propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of therapies targeting cellular aging.

Abstract The prevalence of clonal hematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. We previously reported gene specific fitness effects in two longitudinal cohorts of aging. We now set out to define fitness effects across three longitudinal cohorts of aging in a total of 713 participants. We found that fitness correlates with timing of mutations, which needs to be taken into account when predicting health outcomes. We show that fitness and the time of mutations are superior predictors of outcomes such as all-cause mortality compared to the commonly used clone size (variant allele frequency). Our new predictor even outperforms age, the most important predictor for the onset of age-related disease thus far. In conclusion, the fitness landscape of mutations and their context in terms of clonal composition and timing of mutation acquisition are important parameters to bring CH predictors into the clinic.

Abstract Senescent cells accumulate in nearly all organs with advancing age. A defining characteristic of senescent cells is a robust and heterogenous senescence-associated secretory phenotype (SASP). The SASP influences tissue health and function locally and systemically, hence, circulating components of the SASP may be informative of senescent cell burden. We established a candidate panel of senescence biomarkers based on common cytokines, chemokines, matrix remodeling proteins, growth factors and other proteins components of the SASP. In this seminar, the associations between senescence biomarkers and clinical manifestations of biological age, including frailty, functional limitations, and chronic disease, in humans will be presented. Moreover, the responsiveness of senescence biomarkers to interventions that counter the biology of aging, including exercise and caloric restriction, will be highlighted. Finally, the strengths and limitations of this approach and new directions will be discussed.

Abstract Dementia caregivers are at heightened risk for developing mental and physical health problems. Interventions designed to protect caregiver health often create additional demands on time and energy (e.g., exercise programs). Technology-based interventions (e.g., remote monitoring) can be effective, scalable, and do not add greatly to caregiver burden. Through a collaboration with a local technology company, Care Daily, we conducted two randomized controlled trials to evaluate People Power Caregiver (PPCg), a system of sensors in the home connected to cloud-based AI that alerts caregivers about worrisome deviations from normal patterns (e.g., care-recipient’s falls, wandering). Across two studies (study 1: 9-month duration with professional installation of PPCg; study 2: 6-month duration with caregiver self-installing the PPCg using remote tech support), 284 caregivers were recruited; 261 completed initial study deployment (e.g., system installation); and 235 completed the entire study protocol. Use of PPCg was associated with (a) reduced caregiver anxiety in study 1; (b) greater protection from declines in sleep efficiency in studies 1 and 2. These findings underscore the promise of technology-based intervention to mitigate health problems in dementia caregivers. However, challenges and complexities in recruitment (e.g., remote consenting both caregivers and care recipients), retention (e.g., due to changes in home environment or caregiving status), system installation (e.g., working with caregivers with less experience using technology), data quality assurance (e.g., invalid sensor data) as well as our efforts to overcome these challenges have been instructive. Lessons learned from these studies can provide useful guidance for future large-scale, technology-based interventions for dementia caregivers.

Abstract Physical inactivity is a modifiable risk factor for Alzheimer’s Disease and Related Dementias (ADRD) that can be remediated using remotely delivered interventions. The 12-week telerehabilitation physical activity behavioral (TPAB) intervention includes receipt of a wearable sensor and weekly discussions about physical activity self-monitoring, goal setting, facilitators, and barriers. TPAB has been shown to be feasible and efficacious in increasing daily steps in older adults. However, evidence is lacking for TPAB’s use for people with MCI and using a dyadic approach (i.e., with their care partners). Results from the first phase of our study include descriptive information from two dyads about (1) dyad member interaction with the wearable sensor (i.e., how knowing the current daily step count impacted activity), (2) how dyad members helped each other overcome individual or shared barriers to daily stepping and (3) how dyad members planned activities together to achieve high daily average stepping. This project quantitatively identified (1) the highest stepping day each week was the same for both dyad members 46% of the time (2) the frequency of both dyad members meeting individual weekly stepping goals was 81% compared to just one dyad member or no dyad member reaching the weekly step goal. This project revealed barriers using wearable sensor technology (i.e., not looking at or wearing the wearable sensor). Our discussion will focus on how to enhance meaningful interaction with technology in dyads to track daily stepping that can be applied to improve behavioral change in people with MCI and care partners.

Abstract Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the senescence-associated secretory phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Senescence is a complex and highly heterogenous phenotype and despite tremendous progress in recent years we are still far from fully understanding it. There is no single, stand-alone marker that allows the identification of senescent cells, posing a challenge to their identification and targeting. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. In my talk, I will first describe some of our recent efforts to accurately map senescent cells in different tissues during aging. Additionally, I will describe how mitochondria contribute to the development of senescence and resistance to cell-death. Finally, I will propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of therapies targeting cellular aging.

Abstract The path from PhD to PI can be a challenging uphill climb, and yet, there a are a multitude of steps one can take to increase the likelihood of securing an independent faculty research position. In this presentation, I will share insights from my path from PhD to PI. I will discuss key activities leading to research independence, including developing a research portfolio, engaging in skill-diversifying career development activities, and building supportive mentor-mentee relationships and networks. I will share my experience preparing for and participating in faculty job interviews, which include finding opportunities, giving job talks, and negotiating. As with research, there are many unknowns and many questions while looking forward to a career as an independent researcher. My goal is to share strategic opportunities and demystify processes to ultimately help others successfully navigate their path to research independence.