Pharmacology and Molecular Therapeutics (PHA)

PHA Contact Info

Uniformed Services University of the Health Sciences
Department of Pharmacology and Molecular Therapeutics
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3223
FAX: (301) 295-3220

Pharmacology and Molecular Therapeutics Labs

Cox Lab

Cote Lab

Day Lab

Feng Lab

Iordanskiy Lab

Kortum Lab

Lucki Lab

Nugent Lab

Shewmaker Lab

Singh Lab

Snow Lab

Snow Lab

Name: Snow Lab

Department of Primary Appointment: Pharmacology
Position: National Faculty
Title:

Profile

Snow, Andrew, Ph.D.	Assistant Professor (USU)	C2013	295-3267
Swadhinya Arjunaraja, Ph.D.	Postdoctoral Fellow (HJF)	C2033	295-9742
Batsukh Dorjbal, Ph.D.	Postdoctoral Fellow (HJF)	C2033	295-9742
Camille Lake	Graduate Student (EID)	C2033	295-9742
Kelsey Voss	Graduate Student (EID)	C2037	295-9744

ONGOING PROJECTS

1. Signal regulation and physiological relevance of specific T cell apoptosis pathways

Snow fig 1

The regulation and eventual contraction of activated T cells during an immune response is critical for maintaining equilibrium in the immune system and preventing unwanted damage to host tissues. Normally, specific apoptosis programs induced by T cell receptor (TCR) restimulation or cytokine withdrawal work to cull the majority of activated effector T cells, leaving a small pool of memory T cells behind to protect against subsequent infections (Fig 1). We now appreciate that genetic defects in lymphocyte apoptosis directly contribute to excess lymphoproliferation in humans. For example, T cells from patients with X-linked lymphoproliferative disease (XLP-1) display a profound defect in T cell receptor restimulation-induced cell death (RICD; also known as activation-induced cell death), a critical self-regulatory apoptosis program that constrains effector T cell expansion. Our lab has defined several biochemical mechanisms by which signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which is lost or mutated in XLP patients, facilitates RICD. Most recently, we led an international collaborative effort demonstrating that inhibition of diacylglycerol kinase alpha (DGKa), a modulatory enzyme with elevated activity in SAP-deficient T cells, presents a viable therapeutic approach for treating EBV-induced fulminant mononucleosis in XLP-1 patients, via restoration of RICD. Collectively, this work underscores the physiological relevance of RICD in preventing excessive T cell accumulation, severe immunopathology and mortality in XLP patients infected with EBV. We continue to investigate how RICD sensitivity is “tuned” via SAP-dependent signals.

We are also investigating novel links between metabolic programming and apoptosis sensitivity in human T cells. Our recent work indicates that while excessive anabolic metabolism (i.e. glycolysis) leaves effector T cells more susceptible to RICD, catabolic metabolism (i.e. autophagy) can protect T cells derived from distinct memory compartments from death induced by cytokine withdrawal. We have delineated specific molecular mechanisms responsible for these changes in cell death sensitivity, and continue to investigate how specific metabolic programs affect T cell viability. Our work illuminates how metabolic changes govern T cell survival, and may explain why certain memory T cells give rise to a larger, more robust effector response (via reduced cell death) that better protects the host when challenged with a pathogen or tumor.

2. Novel immunological disorders linked to mutations in CARD11

Snow fig 2

We discovered that gain-of-function (GOF) mutations in the CARD11 gene cause a rare congenital B cell lymphoproliferative disorder called B cell Expansion with NF-kB and T cell Anergy (BENTA) disease. My laboratory has taken a leading role in the genetic diagnosis and phenotypic characterization of an expanding cohort of BENTA patients (Fig 2). CARD11 encodes a scaffolding protein that links antigen receptor signaling to NF-kB activation in lymphocytes. Unlike the wild-type protein, CARD11 GOF mutants spontaneously oligomerize and drive constitutive activation of NF-kB, contributing to increased proliferation and enhanced survival of both immature and naïve patient B cells. Surprisingly, BENTA patients also exhibit hallmarks of immunodeficiency, including B cell differentiation defects, selective antibody deficiency, and opportunistic viral infections (e.g. molluscum contagiousum, chronic EBV) that reflect impaired T cell responses. Our latest findings pinpoint intrinsic molecular defects in plasma cell differentiation and antibody secretion in activated BENTA patient B cells, despite profound apoptosis resistance that likely explains excessive B cell expansion.

In collaboration with Dr. Joshua Milner (NIH) and others, we are also investigating loss-of-function (LOF) CARD11 mutations in atopic patients with severe eczema. We recently described 4 families with distinct, hypomorphic CARD11 mutations that dominantly interfere with WT CARD11 signaling, resulting in impaired NF-kB and mTORC1 signaling. Extensive structure-function studies of the CARD11 molecule continue in my lab, drawing from an expanding list of natural mutations in human patients. Using cell transfection systems, murine models and primary patient lymphocytes, my lab also continues to investigate how both GOF and LOF CARD11 mutations perturb signaling, differentiation and function of B and T cells.

Symes Lab

COX, BRIAN M., Ph.D.	Professor (USU)	C2127	295-3260
Gouty, Shawn, M.A.	Research Biologist. (USU)	C2067	295-3330

COTE, THOMAS E., Ph.D.	Associate Professor (USU)	C2019	295-3907
Santhappan, Rema, Ph.D.	Research Associate (HJF)	C2022	295-3224

DAY, REGINA, Ph.D.	Professor (USU)	C2023	295-3236
Ognoon, Mungunsukh, Ph.D.	Postdoctoral Fellow (HJF)	C2042	295-9872
McCart, Elizabeth	Research Associate (HJF)	C2048	295-9743
Marquez, Ana	Graduate Student (USU)	C2048	295-3439
Murali, Pavitra	Research Associate (USU)	C2051	295-3438
George, Jeffy	Research Associatre (HJF)	C2051	295-3438

YING-HONG FENG, MD, PhD	Associate Professor (USU)	C2063	(301) 295-3232
Huaiyan Cheng, MD	Research Associate (HJF)	C2063	(301) 295-9859

SERGEY IORDANSKIY, PhD	Assistant Professor	AFRRI-46/4429B	(301) 295-0580
Natallia Mikhalkevich, PhD	Research Associate	AFRRI-46/4429	(301) 295-3730

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Pharmacology and Molecular Therapeutics (PHA)