Center for Gene Regulation in Health and Disease (GRHD)

Kailash Gulshan

Based on the American Heart Association’s 2016 Heart Disease and Stroke Statistics update; by the year 2030, ~ 40 % of the US population is projected to have some form of cardiovascular disease (CVD). Current CVD therapies are based upon LDL lowering via up-regulation of the LDL receptor (statins, PCSK9 antibodies) and cholesterol absorption inhibition (ezetimibe). Although statins have been repeatedly shown to decrease CVD risk, there is still 50 to 70% residual risk even in high dose statin treated subjects; in addition, some patients are intolerant of statins. The long-term goal is to identify the novel pathways that can be targeted for designing therapeutics to treat and prevent CVD.

Deposition of modified low-density lipoprotein (LDL) in the arterial intima induces pro-atherogenic NLRP3 inflammasome and IL-1β release pathway. The Nlrp3 inflammasome is highly activated in advanced human atherosclerotic plaques. Inflammation due to sepsis impairs reverse cholesterol transport (RCT) in humans and the increased cardiovascular disease (CVD) incidences among sepsis survivors is a rising concern.  The CANTOS trial using anti- IL-1β antibody showed a reduction in major adverse coronary events (MACE), a composite of heart attack, stroke and cardiovascular death, in patients with a previous myocardial infarction and with increased levels of C-reactive protein (CRP). These studies suggest the link between inflammation, RCT, and CVD and highlight the role of IL-1β secretion pathways in increasing atherosclerosis and CVD risk. Interestingly, a retrospective analysis of CANTOS trial showed a marked reduction in the hazard ratio (HR) of lung cancer incidence in the treatment group compared with placebo controls.  In addition to CVD, the NLRP3 inflammasome and IL-1β release is also implicated in obesity-induced inflammation/insulin resistance. 

My lab is focused on dissecting role of signaling lipid Phosphatidylinositol 4,5-bisphosphate (PIP2) and Gasdermin D (GsdmD) in CVD and lung cancer. The minor phospholipid “PIP2” has emerged as a major player in the NLRP3 inflammasome pathway due to its role in the release of mature IL-1β. The Nlrp3 inflammasome activation of Caspases leads to cleavage of N-terminal fragment of GsdmD, which promotes formation of membrane pores and IL-1β release from  macrophages. The expression of ABCA1, a cholesterol efflux transporter, in macrophages leads to flop of PIP2 to the cell-surface.  ABCA1 mediated PIP2 flop can decrease binding of GsdmD and cleaved IL-1β to membrane and dampen release of IL-1β from macrophages. We will employ cutting edge technologies such as Crispr-Cas9 mediated genome editing, Bone-marrow transplants, Anti-sense oligonucleotide (ASO) mediated generation of mouse models, Lipid-protein interactions via Mass-spec, RNA seq, and Single cell seq 10X genomics to decipher myeloid specific role of PIP2 and GsdmD in atherosclerosis, lung cancer, and diet-induced obesity.

The lab is actively looking for highly motivated Ph.D candidates, techs, and postdocs to join us in these exciting and impactful studies funded by NIH and Case Comprehensive Cancer Center.

 

  • C. Alicia Traughber
    C. Alicia Traughber
    Postdoc
    Location: 
    SR256
    216-687-2480
  • Mariam Raheem Khan
    Mariam R Khan
    Ph.D. candidate
    Location: 
    SR 256
    216-687-2480

Complete List of Published Work in MyBibliography

Selected publications:

Opoku E, Traughber CA, Zhang D, Iacano AJ, Khan M, Han J, Smith JD, Gulshan K*. Gasdermin D Mediates Inflammation-Induced Defects in Reverse Cholesterol Transport and Promotes Atherosclerosis. Front Cell Dev Biol. 2021;9:715211. (*Corresponding author)

Traughber CA, Opoku E, Brubaker G, Major J, Lu H, Lorkowski SW, Neumann C, Hardaway A, Chung YM, Gulshan K, Sharifi N, Brown JM, Smith JD. Uptake of high-density lipoprotein by scavenger receptor class B type 1 is associated with prostate cancer proliferation and tumor progression in mice. J Biol Chem. 2020 Jun 12;295(24):8252-8261.

Brubaker G, Lorkowski SW, Gulshan K, Hazen SL, Gogonea V, Smith JD. First eight residues of apolipoprotein A-I mediate the C-terminus control of helical bundle unfolding and its lipidation. PLoS One. 2020;15(1):e0221915.

Iacano AJ, Lewis H, Hazen JE, Andro H, Smith JD, Gulshan K*. Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release. Sci Rep. 2019 Jul 31;9(1):11128. (*Corresponding author).

Gulshan K*, Brubaker G, Conger  H, Wang S, Zhang R, Hazen SL, Smith JD*. PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly. Circ Res. 2016 Sep 16;119(7):827-838. (*Corresponding author).

Wang S, Robinet P, Smith JD, Gulshan K*. Free-cholesterol-mediated autophagy of ORMDL1 stimulates sphingomyelin biosynthesis.  Autophagy, 2015, 11(7):1207–1208. (*Corresponding author).

Wang S, Robinet P, Smith JD, Gulshan K * ORMDL orosomucoid-like proteins are degraded by free-cholesterol-loading-induced autophagy (*Corresponding author). PNAS. 2015;112(12):3728-3733.

Thakur JK, Arthanari H, Yang F, Pan S, Fan X, Breger J, Frueh D, Gulshan K, Li DK, Mylonakis E, Struhl K,  Moye-Rowley WS, Cormack BP, Wagner G, Näär AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008 Apr 3;452(7187):604-609.

Gulshan K, Moye-Rowley WS. Multidrug resistance in fungi. Eukaryot Cell. 2007 Nov;6(11):1933-1942.