This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. As a ubiquitous lysosomal pathway essential for degrading and recycling proteins and organelles, autophagy has been implicated in a broad spectrum of human disease including cancer, infection, liver disease, myopathy and neurodegeneration. However, the molecular machinery comprising the mammalian autophagy pathway and the molecular mechanism of how this machinery functions are largely unknown. Our long-term goal is to understand the molecular mechanism of the mammalian autophagy pathway and its relevance to human disease, for discovering much needed early diagnostic biomarkers and therapeutic targets. To achieve this goal, our overall objective is to first identify novel protein-protein interactions in the mammalian autophagy pathway and subsequently to determine the functions of these novel interactors. Beclin 1, the first reported mammalian autophagy protein, plays an important positive role in autophagy regulation and has been implicated in a variety of human physiology and pathology, including tumor suppression, neurodegeneration, development and aging. Therefore, for this study, we will investigate Beclin 1-mediated autophagy regulation so as to begin deciphering the molecular mechanism of mammalian autophagy. Guided by strong preliminary data, three specific aims will be pursued using a combination of a novel integrated mouse genetic-proteomic approach as well as biochemical and cell biological studies.
In Aim 1, we will establish the framework of a context-dependent mammalian autophagy interactome through identifying Beclin 1-interacting proteins from living animals;
in Aim 2, we will elucidate the molecular details of autophagy regulation by two novel Beclin 1-interacting proteins, Atg14L and Rubicon;and in Aim 3, we will explore the molecular details of autophagy regulation by a third novel Beclin 1-interactor and its cancer relevance. By establishing the framework of the mammalian autophagy interactome and unraveling the molecular details of autophagy regulation by Beclin 1 and its interacting proteins, this proposed work will not only provide insight into the role of autophagy in mammals but also generate novel potential targets for preventive and therapeutic interventions that may ultimately aid patients suffering from autophagy-related human disease.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Frasinyuk, Mykhaylo S; Zhang, Wen; Wyrebek, Przemyslaw et al. (2017) Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4). Org Biomol Chem 15:7623-7629
Shrestha, Sanjib K; Kril, Liliia M; Green, Keith D et al. (2017) Bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones: New classes of antibacterial/antifungal agents. Bioorg Med Chem 25:58-66
Burikhanov, Ravshan; Hebbar, Nikhil; Noothi, Sunil K et al. (2017) Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis. Cell Rep 18:508-519
Kenlan, Dasha E; Rychahou, Piotr; Sviripa, Vitaliy M et al. (2017) Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells. Mol Cancer Ther 16:831-837
Cifuentes-Muñoz, Nicolás; Sun, Weina; Ray, Greeshma et al. (2017) Mutations in the Transmembrane Domain and Cytoplasmic Tail of Hendra Virus Fusion Protein Disrupt Virus-Like-Particle Assembly. J Virol 91:
Edgar, Rebecca J; Chen, Jing; Kant, Sashi et al. (2016) SpyB, a Small Heme-Binding Protein, Affects the Composition of the Cell Wall in Streptococcus pyogenes. Front Cell Infect Microbiol 6:126
Matveeva, Elena; Maiorano, John; Zhang, Qingyang et al. (2016) Involvement of PARP1 in the regulation of alternative splicing. Cell Discov 2:15046
Furman, Jennifer L; Sompol, Pradoldej; Kraner, Susan D et al. (2016) Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury. J Neurosci 36:1502-15
Huang, Yunjie; Joshi, Smita; Xiang, Binggang et al. (2016) Arf6 controls platelet spreading and clot retraction via integrin ?IIb?3 trafficking. Blood 127:1459-67
Jeoung, Myoungkun; Jang, Eun Ryoung; Liu, Jinpeng et al. (2016) Shoc2-tranduced ERK1/2 motility signals--Novel insights from functional genomics. Cell Signal 28:448-459

Showing the most recent 10 out of 265 publications