Full Projects

2025 Full Project Awardees

Melinda Diver
Physiological roles and molecular mechanisms of SLC37 family sugar-phosphate transporters

Solute carrier (SLC) proteins are critical gatekeepers of metabolite transport across cell membranes, with key roles in metabolism, signaling, and overall cell health. However, progress in identifying their substrates and functions has lagged due to their sheer number, diversity, complexity, and a lack of integrated strategies that combine cellular and molecular approaches. This proposal focuses on the SLC37 family, which includes SLC37A4, a glucose-6-phosphate transporter mutated in glycogen storage disease. It aims to define SLC37 substrates, cellular functions, and structural mechanisms to advance our understanding of their impact on human health and disease.

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Craig Thompson and Richard Hite
Exploring how interactions between distinct metabolic enzyme filaments maintain mitochondrial ATP production and reductive biosyntheses under changing environmental conditions

Mitochondria are the powerhouse of the cell. They produce nearly all the energy a cell uses to maintain its survival. Most of that energy is supplied to the rest of the cell as ATP and used to support RNA and protein production, electrolyte homeostasis, and cell motility, as well as other cell-type specific functions. The remaining energy produced is used by the mitochondria themselves to build precursors required to build proteins and nucleic acids. How mitochondria balance the energy they export as ATP with the energy they retain to build critical cellular building blocks is poorly understood. We have discovered that when the cellular demand for ATP increases, mitochondria divide into two independently-regulated subpopulations - one devoted to ATP synthesis and a second devoted to production of molecular precursors. This proposal will provide mechanistic insights into how this process of functional segregation is regulated and how defects in this process contribute to diseases including premature aging, fibrosis, and degenerative diseases.

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Michael Glickman and Stewart Shuman
Elucidation of a dedicated DNA crosslink repair pathway in bacteria

Mycobacteria are bacteria that includes the human pathogen Mycobacterium tuberculosis, its avirulent relative Mycobacterium smegmatis, and the cancer immunotherapy BCG. Mycobacterial DNA repair pathways play a key role in maintaining genome integrity, though they can also promote mutagenesis. This project focuses on a new pathway of DNA inter-strand crosslink (ICL) repair that we discovered anchored by the homotetrameric Lhr helicase and the Nei2 DNA glycosylase/lyase. Interstrand crosslinks are a common form of DNA damage across domains of life and are the basis for the cytotoxic effect of several chemotherapeutic agents. Through detailed characterization of this pathway biochemically and in bacterial cells we will elucidate the strategies by which mycobacteria contend with ICL damage and define new mechanisms of crosslink repair, potentially relevant to all organisms that cope with this widely distributed form of DNA damage.

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2024 Full Project Awardees

Christine Mayr
3′UTR-dependent control of β-catenin activity during differentiation

Genes encode proteins, which regulate nearly all processes in cells. However, only approximately half of gene sequence is used to generate proteins and it is largely unclear, for what the other is used. We found that the other half regulates protein activity, and we will investigate how protein activity is regulated, with the goal of developing new RNA therapeutics that target protein activity.

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Alexander Rudensky & Thomas Norman

Towards an Integrated Model of Tissue Repair and Defense  

Adaptive tissue responses to perturbations require coordination between the structural components of epithelial and mesenchymal origin and the migratory immune cells. This proposal aims to elucidate the complex intercellular signaling networks evoked during tissue responses to perturbations by investigating the effects of combinatorial signaling on emergent cell states across key tissue cell types that may shape tissue level responses and thereby reveal novel strategies underlying effective tissue defense and repair.

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2023 Full Project Awardees

Heeseon An    
Redefining the Role of Individual Ribosomal Proteins to Elucidate Heterogenous Ribosomes

Although it is known that r-proteins contribute to ribosome biogenesis, their role in protein translation is not clearly understood. Recently, my lab developed a novel tool, ‘Ribo-DART,’ that enables us to re-evaluate r-protein functions by decoupling their roles ‘during’ and ‘after’ the ribosome biogenesis. By using this tool, we aim to investigate ribosomes with altered r-protein compositions, which are associated with various human diseases.

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Mary Baylies  
Development of a Human Pluripotent Stem Cell-derived Skeletal Muscle-Motoneuron Microtissue to investigate Mechanisms Driving Muscle Dysfunction in Nemaline Myopathy

While skeletal muscle plays a critical role in human health, the direct study of human skeletal muscle development has been hindered due to the lack of suitable cell-based platforms. We will develop advanced 3D skeletal muscle-motoneuron microtissues from human pluripotent stem cells that accurately mimic human muscle development from embryonic to adult stages. The aims proposed will provide valuable human stem cell methodologies to an emerging area of muscle biology, new insights to actin regulation during muscle differentiation, and new avenues to understand and potentially treat a muscle myopathy for which there are no therapies. 

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John Petrini & Dinshaw Patel    
Structural and functional studies of the Saccharomyces Cerevisiae Mre11 complex, A Major Effector of the DNA Damage Response

The Mre11 complex is integral to all aspects of the cellular response to DNA damage. This proposal is focused on understanding the structural basis for the various functions of the complex, including its ability to activate DNA damage signaling and DNA repair. After extensive genetic analyses of complex, the structural information obtained will illuminate the mechanisms that underlie the various phenotypes.

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2022 Full Project Awardees

Andrea Schietinger    
Autoimmune Stem-Like T cells and Their Niches

Type 1 diabetes results from the breakdown of tolerance mechanisms in β-cell-specific T cells, but many aspects remain enigmatic, including where and how autoimmune β-cell-specific T cells arise and are maintained. Utilizing a clinically relevant mouse model of autoimmune type 1 diabetes we recently discovered a stemlike T cell population in the pancreatic lymph node which continuously generates β-cell-destroying autoimmune T cells. We propose to use innovative technologies and approaches to define the spatial organization regulating autoimmune T cell differentiation, and test whether modulation of transcription factors associated with the stem-like T cell state disrupts stemness and differentiation, thereby preventing type 1 diabetes.

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Derek Tan    
New Methods for Direct Conversion of Carboxylic Acids to Oxetane Bioisosteres

Oxetanols are a type of chemical motif that can be used to mimic carboxylic acids in drug molecules and have improved pharmacological properties.  However, investigation of oxetanols remains limited due to challenges in chemical synthesis.  To address this problem, we are developing new chemical methods to convert carboxylic acids directly to the corresponding oxetanols using a process called photoredox catalysis.

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Xiaolan Zhao & Dinshaw Patel    
Mechanisms of Smc5/6 engagement and manipulation of DNA

Smc5/6 is a multi-functional genome guardian that promotes faithful DNA replication and repair and response to genotoxins. This collaborative investigation aims to obtain high resolution cryo-EM structures of Smc5/6 in its multiple functional states when engaged with different forms of DNA to understand how these different states influence specific genome maintenance processes.

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2021 Full Project Awardees

Alexandros Pertsinidis    
Laying the foundations for in situ structural biology

Methods that can produce atomic resolution structures of isolated, purified macromolecules using cryogenic transmission electron microscopy (cryoTEM) have recently revolutionized structural biology. Electron microscopy could also in principle visualize macromolecules in their native setting inside the cell, however technical limitations currently preclude high-resolution structural analyses in molecularly crowded and highly heterogeneous environments, The major goals of this project are to develop new methods for single-particle analysis by cellular cryoTEM, to unlock structural characterization of macromolecular machines and assemblies that power cellular life.rget stiffness and whether this mechanosensory behavior alters their transcriptional state.

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Dirk Remus & Richard Hite    
Structural Basis For The Inhibition Of Eukaryotic DNA Replication Fork Progression By G-Quadruplexes

Rapid, complete and accurate DNA replication is integral to the maintenance of the genetic information encoded in chromosomal DNA. However, certain DNA sequences are prone to adopt non-canonical secondary structures that threaten genome integrity by impeding the DNA replication process in ways that are poorly understood. Leveraging the complementary expertises of the laboratories of Richard Hite in structural biology and Dirk Remus in DNA replication, this project will combine structural, biochemical and genetic approaches to determine how G-quadruplexes, a class of abundant DNA secondary structures that form in G-rich regions across the genome, impede the progression of eukaryotic DNA replication forks.

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2020 Full Project Awardees

Lydia Finley
Identifying novel mechanisms of metabolic regulation of cell fate decisions

 Intracellular metabolites can regulate important cellular functions including self-renewal and differentiation, but how metabolites exert these regulatory effects is largely unknown. The goal of this research project is to use chemical and genetic approaches to identify the molecular mechanisms by which metabolites control cell fate decisions. By combining hypothesis-driven approaches with unbiased profiling, the proposed systematic assessment of metabolite effectors will identify novel targets of metabolic control and open new avenues for understanding the impact of the cellular metabolome on fundamental cellular processes.

 

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Morgan Huse     
Mechanoregulation of macrophage phagocytosis

Phagocytosis plays a central role in both immunity and tissue homeostasis by enabling the uptake of pathogens and cellular debris. Although much is known about the chemical signals that regulate phagocytosis, how physical properties like rigidity influence the process is poorly understood. This project will leverage recently developed microfabrication technology to determine whether phagocytic cells respond to variations in target stiffness and whether this mechanosensory behavior alters their transcriptional state.

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2019 Full Project Awardees

Scott Keeney and Dinshaw Patel    
Elucidating the structural and functional principles of germline genome transmission    

A fundamental question in eukaryotic biology is how organisms transmit their genomes—shuffled but undamaged—across sexual generations. Homologous recombination during meiosis plays a central role in this genetic transmission, but despite over a century of study the underlying molecular mechanisms remain poorly understood because of a paucity of biochemical and structural information. This project will tackle this longstanding challenge by bringing together two labs with complementary expertise in meiotic recombination (Keeney) and structural biology (Patel). These groups will study how recombination-promoting proteins work by combining biochemical and structural studies of purified proteins with novel genetic and cell biology experiments in baker’s yeast and in mice.

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Philipp Niethammer    
Probing the role of inflammatory fatty acid metabolism in innate immune memory formation

The project studies how leukocytes, which make the first line of our immune defenses against invading microorganisms, can “remember” past challenges, such as tissue injury and infection, to respond more aggressively to alike challenges in the future. By combining intravital imaging of antimicrobial leukocyte responses in intact zebrafish larvae with current genetic and epigenetic techniques, we seek to unravel the cellular and metabolic basis of “innate immune memory” formation in a developing vertebrate, whose antibody-based, adaptive immune mechanisms have not yet become operant. The expected insights could open new avenues for modulating leukocyte responses for therapeutic advantage during inflammatory diseases and cancer.

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Lestyn Whitehouse    
Molecular indexing of chromatin

The overall goal of this research project is to develop new methodology to identify proteins and DNA that interact in 3-dimensional space. Our technology relies on new methods that allow us to uniquely tag and then identify interacting molecules within a population of billions. We will use this new methodology to address fundamental unanswered questions in the transcription and genome integrity fields: we focus on RNA Polymerase II and aim to learn how transcription is regulated in the context of chromatin and how transcription may interfere with DNA replication. Our method is novel, does not require specialized equipment, and can be readily adapted to study any protein that interacts with the genome.

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We expect there to be two calls for BRIA pilot projects, and one call for full applications each year. Revisions of projects will be considered as new submissions.