Axonal transport is essential for delivering organelles and proteins in neurons. Defects in its components, like kinesin, dynein, microtubules, and tau, can lead to neurodegenerative diseases such as Alzheimer’s and ALS. Our lab studies how post-translational modifications of kinesin and tubulin, and tau isoforms regulate this transport under normal and pathological conditions using molecular biology and imaging techniques. Recent findings indicate that microtubule structure affects tau's inhibition of kinesin transport in an isoform-specific way. Current projects aim to: 

1. uncover how tau isoforms influence kinesin on different microtubule structures;
2. correlate tau isoform distribution with kinesin and microtubule function;
3. explore the effects of tau mutations and modifications related to neuronal diseases; and
4. investigate the impact of tau or kinesin phosphorylation on bidirectional cargo transport.

Most lab projects use crystallography to explore protein structure-function relationships and cofactor interactions. We studied the prothrombinase complex with Dr. Kenneth Mann, focusing on factor Va's structure and its role in thrombin generation. Current efforts involve crystallizing this complex and computer modeling to generate testable hypotheses.

In partnership with Dr. Anne B. Mason, we are investigating transferrin's structure and its receptor, aiming to clarify the pH and iron binding relationships through detailed structural studies.

With Dr. Robert Hondal, we've examined thioredoxin reductases, revealing functional differences between Drosophila and mammalian TRs based on our structural findings.

Ongoing collaborations with Kathleen Brummel-Ziedins, Thomas Orfeo, and Kenneth Mann concentrate on mathematical modeling of coagulation, enhancing our foundational model.

My research group has studied tRNA and aminoacyl-tRNA synthetases (ARSs) for nearly three decades, making key discoveries such as minimal tRNA substrates and mechanistic differences between ARS classes. We've linked mutations in histidyl-tRNA synthetase (HARS) to type IIIb Usher Syndrome and found that threonyl-tRNA synthetase (TARS) promotes angiogenesis when secreted by endothelial cells. Over the past 8-10 years, we've expanded collaborations to explore ARS mutations connected to neuropathies and CNS disorders. Future work aims to use our insights on HARS and Usher Syndrome in zebrafish models to investigate ARSs' roles as nutritional sensors in neurogenesis.

Even though the DNA in all of our cells is nearly the same, it is epigenetic factors, including modifications to DNA, RNA, and chromatin, that control the gene expression patterns in different cells, under various environmental conditions, and at specific times. Post-translational modifications on histone tails function as a very complex code for controlling gene expression. Deciphering this code is at least as important as the genetic code for understanding its role in stem cell programming, maternal effects during fetal development, and potential reversibility in cancer therapies. However, it is also orders of magnitude more complex. We study the molecular mechanisms driving the recognition of histone modifications, and how combinations of these chemical signals regulate protein interactions on the nucleus in both normal and disease states.

Our research focuses on high-risk pediatric leukemia, particularly those with chromosomal translocations involving the AF10 transcription factor. We aim to identify and test novel targeted therapies for aggressive CALM-AF10 leukemias, exploring alterations in cell-stroma adhesion and the aberrant expression of key adhesion mediators. We are conducting studies that combine targeted therapies with traditional chemotherapy. Additionally, we are using next-generation sequencing to investigate the role of the AF10 transcription factor, which is involved in several leukemogenic translocations but remains poorly understood.

My research group studies the redox chemistry of sulfur and selenium, focusing on selenocysteine, the 21st amino acid. We explore why selenocysteine is crucial, identifying its roles in resisting oxidation, preventing electrophilic modification, and facilitating one-electron reductions. Recently, we have examined ergothioneine, a potential vitamin produced by fungi and bacteria, which is linked to reduced cardiovascular disease and dementia risk when present at low levels. We discovered that selenocysteine-containing thioredoxin reductase can reduce oxidized ergothioneine, suggesting a potential connection between selenium and ergothioneine.

Dr. Kelm’s research aims to uncover the molecular mechanisms behind the phenotypic reprogramming of heart, blood, and vascular cells affected by disease or injury, utilizing biochemical, biophysical, cellular, and in vivo methods. His lab has identified novel single-stranded nucleic acid-binding proteins that repress genes related to the differentiation of specific muscle, stromal, and leukocyte types. Currently, his team is exploring the roles of Pur-alpha, Pur-beta, and YB-1 in the dysfunctional phenotypic modulation of vascular and myeloid cells linked to arteriosclerosis and hematopoietic malignancy.

ADP-ribosylation modifies proteins, DNA, and RNA in response to signals, relying on the writer PARP1, the eraser PARG, and various readers. This modification is crucial for cell integrity, influencing DNA mechanisms, chromatin structure, signaling, metabolism, mitochondrial homeostasis, and cell death.

The development of PARP1 and PARG inhibitors has clarified their distinct roles, with several PARPi approved for specific ovarian cancer treatments. However, broader therapeutic application is hindered by a limited understanding of ADP-ribosylation. Our long-term goal is to deepen insights into its role in cell homeostasis.

The prothrombinase complex, a Ca2+-dependent, membrane-bound assembly of factor Xa and its cofactor factor Va, plays a critical role in hemostasis by generating thrombin. While 80% of factor V is in plasma, the physiologically relevant 20% resides in platelet α-granules, released upon platelet activation at vascular injury sites to enhance clot formation. As part of Dr. Paula Tracy’s research team, I am investigating how the unique structural properties of platelet-derived factor Va contribute to its effectiveness as a cofactor for prothrombinase. We employ various physical and biochemical techniques to characterize post-translational modifications of both plasma- and platelet-derived factor Va, including glycosylation, phosphorylation, sulfation, and lipid anchoring, to correlate these structures with cofactor function. We also explore how platelets modify factor V during endocytosis in megakaryocytes, which will enhance our understanding of cellular trafficking and biological processes. Ultimately, this research aims to inform clinical strategies for managing hemostasis and preventing thrombosis.

Our research program focuses on the epigenetic regulation of cell proliferation and differentiation, particularly in mammalian development and disease. We have pioneered techniques to characterize transcriptional regulation that influences cell cycle control through multi-omic and spatial transcriptomic approaches. Currently, we are exploring the gene regulatory mechanisms governing the G1/S phase transition in normal, tumor, and stem cells.

In skeletal biology, we are leading efforts to understand bone tissue-specific gene expression. Our ongoing research includes the role of microRNAs and long non-coding RNAs, as well as genetic and biochemical factors in skeletal development and bone remodeling related to skeletal diseases and cancer metastasis to bone.

Our work has clarified the functional relationships between the organization of regulatory proteins, chromatin structure, and gene expression. We are investigating how nuclear architecture contributes to epigenetic control of cell fate and lineage commitment, alongside mechanisms like mitotic gene bookmarking and oncofetal epigenetic regulation. These studies aim to define architectural parameters of regulatory networks for developing highly specific therapeutic strategies with minimized off-target effects.

My laboratory investigates the structure and function of protein-DNA complexes essential for DNA replication, homologous recombination, and repair, including double-strand break repair (DSBR). We utilize model systems such as bacteriophage T4, Deinococcus radiodurans, Saccharomyces cerevisiae, and humans. Our methodologies include kinetics, fluorescence spectroscopy, site-directed mutagenesis, single-molecule enzymology, and X-ray crystallography. Current projects encompass:

1. **DNA Helicase Mechanisms**: We study Gp41 and Dda helicases in the T4 replication system. Gp41, a processive helicase, is regulated by Gp59, which coordinates helicase assembly with DNA synthesis. We're investigating Gp59's role through biochemical studies. Dda's function is influenced by T4 ssDNA-binding protein Gp32, and we are exploring how Gp32 affects Dda's kinetics and self-association.

2. **Presynaptic Filament Structure and Function**: We investigate the RecA/Rad51 family recombinases' presynaptic filaments formed on single-stranded DNA during recombination and repair. Our focus is on UvsX and RecA to understand filament dynamics through fluorescence spectroscopy and single-molecule approaches. We have generated Rad51 mutants to explore allosteric communication and co-published the 2.5 Å X-ray structure of an allosteric Rad51 mutant. We continue to create and characterize new allosteric mutants.

3. **Characterization of hRAD51 Tumor Mutants**: We examine tumor-derived mutations of hRAD51 linked to cancer-associated recombination defects. By expressing and purifying these mutants, we aim to assess differences in their DNA binding and enzymatic properties. Our findings will enhance understanding of how tumor cells evade DNA repair, ultimately aiming to inform cancer treatment strategies.

His research focuses on the regulation of active enzyme species in blood coagulation by specific protease inhibitors, cell processes, and pharmacologic agents that control clot formation and breakdown. He employs experimental methods using phlebotomy blood, plasma, and systems of purified proteins to map the sequence of pro- and anticoagulant events that prevent vessel blockage while sealing leaks. The findings are mathematically modeled with ordinary differential equations to expand reaction pathways for better empirical study design and clinical application. Recent work has aimed at understanding abnormal hemostasis in conditions such as radiation injury, burn trauma, and pregnancy.

Our laboratory aims to understand platelet involvement in thrombin generation, which relies on a Ca2+-dependent complex of factor Va and factor Xa. A key goal is to quantify the kinetic and binding events between these factors and the platelet membrane, while identifying the relevant membrane receptors, signaling pathways, and enzymatic processes. Additionally, we seek to elucidate how megakaryocytes regulate the endocytosis and synthesis of factor V(a), as well as its trafficking and phenotypic changes. Understanding how platelets acquire, process, and present factor Va is crucial for regulating thrombin generation, which is essential for normal blood clotting and influences both physiological and pathological processes.