infectious diseases
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The Role of the Intestinal Microbiota in Sepsis Mortality
Project Summary/Abstract Sepsis is a life-threatening condition characterized by a dysregulated host response to infection that can cause multi-organ damage and death. As the leading cause of in-hospital mortality, sepsis mortality rates reach up to 50%, and account for approximately 270,000 deaths and $38 billion annually in health care costs in the United States. Notably, patients with similar medical backgrounds can have vastly different sepsis outcomes— some survive with medical treatment while others die. The reasons for this dichotomy are unknown but is seen across all forms of bacterial bloodstream infections, is not specific to any strain-level differences in the infecting pathogen and cannot be explained by human genetic differences. Human microbiota studies suggest that gut microbial dysbiosis is associated with sepsis mortality and that these alterations influence gut barrier breakdown, leading to gram-negative bacteremia—one of the most common causes of sepsis and mortality. However, there are a lack of studies that investigate the causal role of the intestinal microbiota in sepsis mortality. This K08 proposal will elucidate the role of the intestinal microbiota in sepsis mortality. Utilizing the well- established murine model of sepsis by intraperitoneal injection of lipopolysaccharide (LPS), we combine microbiota taxonomic sequencing and metagenomics, advanced bioinformatic techniques and prediction modeling, with knowledge of mucosal immunity and germ-free mouse systems to characterize the microbiota features and members that correlate with, predict, and cause sepsis mortality. This proposal is organized into two specific aims: (1) identify baseline stool microbial features associated with and predictive of sepsis outcomes and (2) determine how colonization with immunostimulatory microbes heightens sepsis mortality. In this work, I will holistically characterize the host immunologic and microbiota features that are associated with and predictive of mortality and experimentally identify microbes and microbial pathways that cause death in our model. These findings will reveal new microbial and host biomarkers of sepsis mortality and identify novel targets for sepsis prevention and treatment to reduce the overall mortality rate of this deadly disease. My long-term goal is to become an independent physician-scientist who integrates cutting-edge computational methods with experimental biology to identify predictive biomarkers of disease onset and outcomes, investigate how they influence disease processes, and develop novel therapeutic and preventive strategies to improve patient care. This proposal details specific research aims and a structured career development and training plan that will allow me to acquire focused, in-depth and multidisciplinary training under the guidance of an internationally recognized team of experts in clinical infectious diseases, host-microbiota interactions, immunology, immunometabolism, and computational biology. The knowledge generated will address the fundamental role of the microbiota in sepsis outcomes and inform future preventative and therapeutic strategies that will lower the sepsis mortality rate worldwide.
Mentoring investigators in patient-oriented research on HIV and public health
PROJECT SUMMARY/ABSTRACT Despite marked progress in treatment and prevention, HIV remains a significant public health threat in the US and globally. Innovative strategies are needed to effectively deploy interventions and reduce HIV incidence, which requires a sustained and committed workforce. Dr. Dennis is an infectious disease physician and researcher at the University of North Carolina (UNC) at Chapel Hill, Division of Infectious Diseases. She seeks the protected time of the K24 award to ensure adequate time and effort to provide mentorship in patient- oriented HIV research focused on applied public health strategies. Dr. Dennis has a track record of performing high-quality patient-oriented research supported by independent funding. Her research bridges basic, clinical, and epidemiologic science by using HIV-1 molecular epidemiology and phylogenetics to understand HIV transmission at the population level and to use this information to direct prevention. She has expanded this work to optimize strategies to detect and respond to HIV networks using mixed-methods approaches. The overall goal of this work is to uncover the links between these sub-epidemics - which are overlapping sub- epidemics defined by risk groups, geography, social interaction - to facilitate the design of timely, effective interventions. The research specific aims are 1) Investigate HIV transmission networks using molecular epidemiology and phylodynamics (R01AI135970), 2) Evaluate uptake of HIV treatment and prevention services in public health with social network approaches (supported by R01AI169602), and 3) Pilot a network-based characterization of early syphilis infections to inform strategies to increase the uptake of injectable antiretrovirals for HIV treatment and prevention (supported by K24). With the support of the K24, she will leverage resources at UNC to support mentorship and professional development to strengthen new directions (implementation science, community-engaged research). Dr. Dennis is deeply committed to expanding her mentorship and dedicated to fostering diverse mentees with lived experiences that are critical for sustaining the HIV workforce. Dr. Dennis is Co-Director of the UNC Center for AIDS Research (CFAR) Scientific Working Group which focuses on Ending the HIV Epidemic efforts in North and South Carolina. She has strong institutional support and a multidisciplinary team of advisors, including the UNC CFAR, and is an advisor on the UNC T32 HIV/STI institutional training program. She has collaborated for the past 10 years with NC Division of Public Health and with multiple investigators and trainees at the UNC Gillings School of Public Health. She is active in the UNC Infectious Diseases Fellowship program, providing clinical and research mentorship to numerous ID fellows. Her clinical activity provides practical grounding and relevance in patient-oriented research. The K24 will provide 50% of Dr. Dennis’ salary and additional funds to support mentees’ research. The proposed research is timely and aligned with the National HIV/AIDS Strategy and will support the protected time needed to mentor the next-generation of investigators in HIV patient-oriented research.
Prosocial Learning and Motivation across the Lifespan
2024 BACN Early-Career Prize Lecture Many of our decisions affect other people. Our choices can decelerate climate change, stop the spread of infectious diseases, and directly help or harm others. Prosocial behaviours – decisions that help others – could contribute to reducing the impact of these challenges, yet their computational and neural mechanisms remain poorly understood. I will present recent work that examines prosocial motivation, how willing we are to incur costs to help others, prosocial learning, how we learn from the outcomes of our choices when they affect other people, and prosocial preferences, our self-reports of helping others. Throughout the talk, I will outline the possible computational and neural bases of these behaviours, and how they may differ from young adulthood to old age.
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