Collaborators of the CICBDD
Funding Source |
Grant Number |
CICBDD Involvement |
| NIH (NCI) | 1 R01 CA242305-01 | Lindsey James (PI) |
| Dmitri Kireev (Investigator) |
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Funding Source |
Grant Number
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CICBDD Involvement |
| NIH (NIGMS) | R01GM138912 | Samantha Pattenden (PI) |
| Michelle Thomas (Graduate Student, Pattenden Lab) |
Development of a cavitation enhancement technology to access archived tissues for epigenetic-based biomedical research |
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| Innovative new technologies that enable experimentally robust interrogation of epigenetic mechanisms are needed to broaden our understanding of epigenetic regulatory pathways in human development, disease, and therapeutic resistance. Formalin fixed, paraffin embedded (FFPE) tissues contain a wealth of information on human disease, however, extraction of high-quality chromatin (DNA together with associated nuclear proteins) from these samples for use in epigenetic assays has proven virtually impossible. We will explore the use of a unique cavitation enhancement reagent in simplifying and standardizing chromatin extraction from FFPE tissues, with the goal of making archived biospecimens available for a broad range of epigenetic-based biomedical research. | ||||
Funding Source |
Grant Number |
CICBDD Involvement |
| NIH (NCI) | R01CA205398-02 | Xiaodong Wang (Investigator) |
MerTK and the Innate Response to melanoma |
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| MerTK’s macrophage role is to trigger ingestion of apoptotic cells and polarize the innate immune response towards an M2, wound healing phenotype. In melanoma, this produces an immunosuppressive milieu. We are investigating how to inhibit MerTK, reverse immunosuppression and stimulate anti-tumor immunity. | ||||
Funding Source |
Grant Number |
CICBDD Involvement |
| NIH (NCI) | 1 R01 CA249190-01 | Xiaodong Wang (MPI) Dmitri Kireev (MPI) Ken Pearce (Investigator) |
MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity |
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Funding Source |
Grant Number |
CICBDD Involvement |
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| NIH |
1 R01 CA259077-01 | Xiaodong Wang (MPI) | ||
Novel TYRO3 inhibitors for treatment of cancer |
| TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases and is a potential therapeutic target in a wide variety of human tumors. Here, we propose to develop novel, potent, and selective TYRO3 inhibitors and validate their biochemical and functional activities in TYRO3-dependent tumor xenograft models and immune-competent syngeneic cancer models. |
Funding Source |
Grant Number |
CICBDD Involvement |
Novel Bioorthogonal Chemical Epigenetic Modifier Development |
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| This project aims to use novel bifunctional molecules to precisely regulate gene expression in a dose dependent and reversible manner and translate this strategy to clinically relevant targets. | ||||
| Eshelman Institute for Innovation | RX03202106 | Lindsey James (MPI) |
Computational and experimental insights into the structure and dynamics of heterochromatin |
| Three main components of our research are: (i) Development of MB techniques to study complex traits of epigenetic regulation; (ii) Multi-scale simulations of chromatin processes to elucidate the structure and dynamics of heterochromatin of Oct4 regulatory elements; (iii) Experimental real-time monitoring of heterochromatin molecular signatures using Chromatin in vivo Assay (CiA) to study mechanisms and time course of Oct4 de-repression and provide feedback for the computational models. |
| NIH | 1 R01 GM132299-01A1 | Dmitri Kireev (MPI) |
Funding Source |
Grant Number |
CICBDD Involvement |
| NIH (NCI) | 1 R03 CA252796-01 | Samantha Pattenden (Investigator) Ken Pearce (Investigator) |
Targeting ALT-Cancer |
| The long-term goal of the proposed project is to identify the first chemical probes and potential clinical candidates targeting the alternative lengthening of telomeres (ALT) mechanism present in a subset of cancer cells. |
Funding Source |
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CICBDD Involvement |
| NIH /Triangle Biotechnology, Inc. (Tbio) | Samantha Pattenden (PI) |
SBIR: Commercialization of cavitation-enhancing nanodroplets for DNA sample fragmentation in NGS applications |
| TBio and UNC will make nanodroplets and will QC droplets. UNC will make SOPs for 96 sample sonication in Qsonica, Branson, Covaris E220/LE220. TBio will design and manufacture racks. UNC will perform NGS (including bioinformatics) on yeast and human gDNA and compare to Covaris microTUBE and enzymatic digestion. TBio will develop scale-up manufacturing technologies. TBio and UNC will develop non-freeze droplets. UNC will test non-freeze droplets. TBio will perform internal QC and batch/lot testing, shelf-life testing, and shipping stability. TBio will prepare beta kits and perform testing with customers (including UNC). |
Funding Source
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Grant Number |
CICBDD Involvement
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Polycomb Repressive Complexes as Key Regulators of HIV Latency and Targets for Latency Reversal |
| In this proposal we seek to investigate Polycomb regulation of proviral quiescence in HIV infected patients and the role of drugs of abuse in this process in order to advance our current understanding of persistent HIV infection and guide the develop of novel therapeutics, specifically latency reversing agents, toward an HIV cure. |
| NIH (NIDA) | 1R61DA047023-01 | Lindsey James (PI) Dmitri Kireev (Investigator) |
Profiling Chromatin Regulators in HIV latency |
| The goal of this project is to validate and screen novel epigenetic regulators for HIV latency reactivation via combinatorial shRNA/small molecule inhibitor screens and mechanistic studies, as well as corroborate the functional relevance of targeting epigenetic regulators in a primary cell model. |
| Qura Therapeutics | Lindsey James (PI) |
Collaborator |
Affiliation |
Funding Source |
Grant Number |
CICBDD Involvement |
| NIH | R35GM139514-01 | |||
| Cheryl Arrowsmith | SGC-University of Toronto | Stephen Frye (PI) | ||
| Mark Bedford | MD Anderson-University of Texas | Lindsey James | ||
| Oliver Bell | University of Southern California | Dmitri Kireev | ||
| Tatiana Kutateladze | University of Colorado | Ken Pearce |
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| Pengda Liu | UNC-Biochemistry and Biophysics | |||
| Catherine Musselman | University of Colorado | |||
| Greg Wang | UNC-Biochemistry and Biophysics | |||
Maximizing Investigators’ Research Award-Probing Allostery in Methyl Lysine Reader Domains |
| Allosteric interactions in chromatin regulatory complexes are critically important phenomena that create unique opportunities for pharmacologic intervention. The theme of this research will be the development of allosteric modulators of catalytic and nucleic acid binding functions of methyl lysine readers. |
Funding Source |
Grant Number |
CICBDD Involvement |
| NIH | 1R01CA223495-01A1 | Ken Pearce (Investigator) Dmitri Kireev (Investigator) Xiaodong Wang (Investigator) |
A HTS Approach to Discover Guanine Nucleotide-Competitive Inhibitors of Oncogenic KRAS |
| The goal is to use our novel, newly developed fluorescence-based guanine nucleotide displacement assay in a high-throughput screening (HTS) program to search for inhibitors of oncogenic RAS. |
CICBDD Involvement |
Xiaodong Wang (PI) Dmitri Kireev (Investigator) Ken Pearce (Investigator) |
IP Kinase |
| This proposes a collaboration between UNC Chapel Hill and Dr. Stephen Shears at the National Institute of Environmental Health Sciences. The goal of this project is to develop isoform specific inhibitors for IP kinase family. |
Funding Source |
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CICBDD Involvement |
| UNC Lineberger Comprehensive Cancer Center | Dmitri Kireev (Co-Investigator) Ken Pearce (Co-Investigator) |
Development of selective inhibitors to a novel target in progression of castration resistant prostate cancer |
| Recurrence of prostate cancer following androgen deprivation therapy (ADT) has few treatment options and a high mortality rate. Castration resistant prostate cancer (CRPC) is hallmarked by aggressive tumor and metastatic growth that is no longer dependent on circulating testosterone. Prostate cells control potency and availability of androgens in part by inactivating them through the glucuronidation pathway. We have implicated UDP-glucose dehydrogenase (UGDH), which provides the UDP-glucuronate precursor for glucuronidation, as a critical regulator of prostate tumor androgen response, and found that UGDH acts as a sensor that directs precursors to glucuronidation in response to metabolic conditions. We recently implicated a novel kinase as a cellular regulator of UGDH activity through phosphorylation of a serine located at the UGDH subunit contact interface critical for its normal function. The increased understanding of mechanisms controlling the cellular prioritization of UGDH enzymatic activity provides a strong rationale for its potential use as a therapeutic target in prostate cancer. We propose two aims: 1) Determine the efficacy of kinase-UGDH combined inhibition in the control of tumor cell androgen dependence and therapeutic response. We will use a peptide inhibitor of UGDH identified through phage display as proof of concept to demonstrate anti-proliferative effects of pharmacological UGDH targeting in vitro. 2) Use a high throughput approach to identify small molecule lead compounds for selective inhibition of UGDH. The UGDH-binding peptide will be used as a probe to inform small molecule inhibitor discovery by computational and biochemical screening methods. Manipulation of UGDH activity in combination with inhibition of its putative regulatory kinase will support use of the kinase-UGDH “axis” as a selective therapeutic target. |
Funding Source |
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CICBDD Involvement |
| NIH | 1 R01 CA258993-01 | Dmitri Kireev (Investigator) Ken Pearce (MPI) |
A high-throughput platform to identify selective allosteric inhibitors of the PLC~y isozymes |
| We propose to use novel fluorescent substrates to develop assays for high-throughput screens that will identify compounds that selectively inhibit the two human PLC~y isozymes. Validated inhibitors will serve as hit compounds for subsequent development of drug candidate molecules for potential treatment of lymphomas and leukemias driven by constitutively active forms of the PLC~y isozymes. Our drug discovery effort will benefit enormously from our success in determining the first atomic-resolution structure of a full-length PLC~y isozyme. |
Funding Source |
CICBDD Involvement |
| Cure Alzheimer’s Fund |
Dmitri Kireev (Investigator) Ken Pearce (MPI) |
Small molecule activators of PLC~y2 as novel therapeutics for Alzheimer’s disease
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| This project seeks to develop selective activators of PLC~y2 that will likely replicate the protective effects of the gain-of-function variant PLC~y2 (P522R) to attenuate neuroinflammation and slow AD progression. |
Funding Source |
Grant Number |
CICBDD Involvement |
The Chemical Epigenomics Creativity Hub: integrating scientific fields to enable grand discoveries |
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Multidisciplinary, multi-PI project to leverage chemical biology techniques to interrogate epigenetic processes.
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Polycomb Repressive Complexes as Key Regulators of HIV Latency and Targets for Latency Reversal |
| In this proposal we seek to investigate Polycomb regulation of proviral quiescence in HIV infected patients and the role of drugs of abuse in this process in order to advance our current understanding of persistent HIV infection and guide the develop of novel therapeutics, specifically latency reversing agents, toward an HIV cure. |
| NIH (NIDA) | 1R61DA047023-01 | Lindsey James (PI) Dmitri Kireev (Investigator) |
Collaborator |
Affiliation |
Funding Source |
Grant Number |
CICBDD Involvement |
| Greg Carter, Bioinformatics Core Lead | The Jackson Laboratory | NIH/Emory University | U54AG065187-01 | Alison Axtman (Medchem Core PI) |
| Aled Edwards, MPI, Admin/Data Core | SGC-University of Toronto | Ken Pearce (Investigator) | ||
| Alison Axtman, MPI Med Chem Core Lead | UNC at Chapel Hill | Xiaodong Wang (Investigator) | ||
| Halan Fu, MPI, Assay Core Lead | Emory University | Dmitri Kireev (Investigator) | ||
| Opher Gileadi, MPI, Struc Bio Core Lead | SGC-University of Oxford | Kevin Frankowski (Investigator) |
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| Allan Levey, MPI, Admin/Data Core | Emory University | Jeff Aubé (Investigator) |
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| Ben Logsdon, Bioinformatics Core Lead | Sage Bionetworks | Tim Willson (SGC) (Investigator) | ||
| Frank Longo, MPI, Admin/Data Core | Stanford University | |||
| Lara Mangravite, MPI, Admin/Data Core | Sage Bionetworks |
| Larsson Omberg,Data Core Lead | Sage Bionetworks |
TREAT-AD |
| The overarching goal of this program is to develop and openly distribute the experimental tools necessary for the academic research community to test a wide range of therapeutic hypotheses for Alzheimer’s disease (AD). Targets will be nominated from across the research field and prioritized by our team of experts who will inform prioritization through a combined expertise in AD biology, clinical translational studies, neuropathology, genetics, and bioinformatics. |
Funding Source |
Grant Number |
CICBDD Involvement |
Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target |
| The goals of this project are to validate the MAGEA4-RAD18 DNA repair pathway as a therapeutic target using pre-clinical mouse models and to generate small molecule inhibitors of the MAGEA4-RAD18 complex that sensitize cancer cells to DNA-damaging therapies. |
| NIH-NCI | R01 CA229530-01A1 | Ken Pearce (MPI) Albert Bowers (MPI) Dmitri Kireev (Investigator) |
Pathological Reprogramming of DNA Damage Signaling in Neoplastic Cells |
| The goal of this project is to define the molecular mechanisms by which Cancer Testes Antigens (CTAs) pathologically reprogram genome maintenance pathways to stimulate mutagenesis and carcinogenesis in response to environmental genotoxic exposures. |
| NIH/NIEHS | R01 ES029079-01A1 | Ken Pearce (MPI) |