Robert G. Kalb Neuronal Biology Laboratory @ CHOP
Robert G. Kalb, MD, is a research scientist at The Children’s Hospital of Philadelphia and a professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania.
Robert Kalb, Robert G. Kalb, Kalb Neurology, CHOP, Children's Hospital of Philadelphia, University of Pennsylvania, Kalb Neuronal Biology Laboratory, Joseph Stokes Jr. Research Institute, University of Pennsylvania School of Medicine, Kalb, Neurology, CHOP Neurology, Neurology Research, ALS Research, SMA Research, Dr. Kalb, Bob Kalb
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Kalb Neuronal Biology Laboratory

About the Lab

Kalb Neuronal Biology Laboratory
The Joseph Stokes Jr. Research Institute
The Children’s Hospital of Philadelphia
University of Pennsylvania School of Medicine

One of the major aims of our work is to investigate the cellular and molecular events underlying the development of the vertebrate central nervous system. In particular, we study how synaptic activity guides the formation of neuronal architecture and synaptic connectivity. We are actively studying the role of specific glutamate receptor subunits and downstream signaling cascades. In these investigations we focus on the spinal cord, with particular emphasis on motor neuron development.

Our laboratory also examines the control of sensitivity of motor neurons to toxic insult. Using tissue culture models we are investigating the ability of trophic factors to render motor neurons vulnerable to insult. The intracellular signaling systems that are involved in this phenomenon are actively studied in our lab.

These avenues of research are relevant to a number of clinical conditions including spinal cord injury (i.e., traumatic, ischemic) and motor neuron diseases (i.e., amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)). Translation of our experimental work into new therapies for these disorders is our primary long-term goal.

Resources

These are some of the resources in the lab:

  • Laser Confocal Microscope
  • Standard fluorescence and bright field microscopes
  • qPCR machine
  • Seahorse metabolic flux machine
  • PCR machines
  • Full tissue culture facility
  • Stereodissecting microscopes, some with fluorescence capability
  • Inverted microscope and injection setup for generating transgenic C.elegans
  • Standard lab equipment for protein chemistry, molecular biology, etc
  • Virus capacity for over expression or knockdown of genes in neurons in vitro
  • Somatic transgenesis of rodents using neonatal AAV administration
  • Various cell lines, MEFs, etc.
  • C.elegans strains (hundreds) and feeding RNAi libraries
  • Various transgenic, knockout and conditional knockout mice
Techniques

These are some of the techniques we use:

  • Primary neuron tissue culture
  • Metabolic flux assays
  • Cloning
  • RNA analysis
  • Protein analysis
  • Quantitative microscopy for analysis of dendritic trees and synapses
  • Quantitative microscopic analysis of C.elegans locomotion and synapses
  • Generation of iNeurons
  • C.elegans genetics
  • Mouse behavioral assessment battery
  • Mass spectrometry

Interested in learning more about our work, partnering with us, or joining our team?

Meet The Team

Robert G. Kalb, CHOP Neurology
Dr. Robert G. Kalb, MD

Director

Robert G. Kalb, MD, is a research scientist at The Children’s Hospital of Philadelphia and a professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania.

Senior Scientists

Post-Doctoral Fellows

Jelena Mojsilovic-Petrovic MD, PhD

Jelena Mojsilovic-Petrovic MD, PhD

Lei Zhang MD, PhD

Lei Zhang MD, PhD

Heather Bennett PhD

Heather Bennett PhD

Chia-Yen Wu PhD

Chia-Yen Wu PhD

Neuroscience Graduate Group, PhD Students

UPenn Undergraduates

Shachee Doshi

Shachee Doshi

Preetika Gupta

Preetika Gupta

undergrads

Left to Right: Rahul Gupta, Matt Lan, Ogul Uner

Our Partners & Supporters

Recent Updates

  • Matt and Rahul having fun

    Matt and Rahul are applying their creativity to making a dot blot apparatus.  I believe the light source under...

  • Summer Students

    Great news!  Two superb undergraduate students will be working in the lab with summer: Justin Landis and Emma ...

  • Preetika

    Preetika made a neat observation  the other day.  In our SAP97 conditional KO mouse there is a compensatory in...

Our Projects

Activity-dependent development

SAP97 – The AMPA receptor subunit GluA1 forms a physical complex with the SAP97 protein in the post-synaptic density. There, GluA1/SAP97 translates activity of glutamatergic synapses into dendritic growth and specification of connectivity within a network. We are currently studying the role of this complex in the forebrain using a conditional knockdown mouse. The approaches we are taking include mouse behavior, anatomy and molecular.

CRIPT – One SAP97 binding partner of interest that we have identified is the cysteine rich interactor of PDZ3 (CRIPT). We are studying the mechanism by which CRIPT participates in GluA1/SAP97 dependent developmental events.   CRIPT is a fascinating protein and loss of function mutations lead to a devastating developmental neurological disorder.

Zhou, Weiguo. Zhang, Lei. Guoxiang, Xiong. Mojsilovic-Petrovic, Jelena. Takamaya, Kogo. Sattler, Rita. Huganir, Richard. Kalb, Robert.: GluR1 controls dendrite growth through its binding partner, SAP97. Journal of Neuroscience 28(41): 10220-33, Oct 8 2008

White, S., Ortinski, P., Shayna H., Friedman, S.H., Neve,R. L., Kalb, R. G., Schmidt, H.D., and Pierce, R. C. A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking. Neuropsychopharmacology doi: 10.1038/npp.2015.199, (2015)

Zhang, L., Hsu,F.-C., Mojsilovic-Petrovic, J., Jablonski, A.M., Zhai, J., Coulter, D.A. and Kalb, R.G. Structure-Function Analysis Of SAP97, A Modular Scaffolding Protein That Drives Dendrite Growth. Mol. Cell. Neurosci 65:31-44, (2015).

Boccitto, M., Doshi, D. , Newton, I.P., Nathke, I., Neve. R., Mao, Y., Zhai, J., Zhang, L., and Kalb, R.G. Opposing Actions of the Synapse Associated Protein of 97 kDa Molecular Weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/b-catenin Signaling. Neuroscience 2016 (in press).

 

Proteotoxicity and neurodegeneration

Loss of protein homeostasis (proteostasis) is a common underlying pathological event in all neurodegenerative diseases. In a screen for proteotoxicity suppressors undertaken in C.elegans, we have identified rad23 as a gene of interest. We find that loss of rad23, both in worms and in mammalian neurons is neuroprotective and this is associated with accelerated degradation of misfolded proteins. We are interested in understanding the mechanism by which rad23 acts as an “anti-chaperone”.

Jablonski, A.M., Lamitina, T., Liachko, N.F., Sabatella, M., Liu, J., Zhang, L., Ostrow, L.W., Gupta, P., Wu, C.-Y., Doshi, S., Mojsilovic-Petrovic, J., Lans, H., Wang, J., Brian C Kraemer, B.C., and Kalb, R.G.. Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance. J Neurosci 34:14,286-14,306 (2015).

Periz, G., Jiayin Lu, J.,Zhang, T., Mark W. Kankel, M.W., Jablonski, A.M. Kalb, R. G., McCampbell, A., Wang. J. Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription PloS Biol DOI: 10.1371/journal.pbio.1002114 (2015)

 

Hypoxia at the whole animal level

Hypoxic insult at the time of birth (asphyxia) is a major cause of morbidity and mortality worldwide. Using C.elegans, we have defined a new pathway that confers resistance to hypoxic insult during development.

Flibotte, J.J., Jablonski, A.M. and Kalb, R.G. Oxygen sensing neurons and neuropeptides regulate survival after anoxia in developing C. elegans. PloS One 9;e101102 (2014)

Suppressors of Spinomuscular Atrophy

Spinomuscular Atrophy (SMA) is a major motor neuron disease of infants and children. It is caused by loss of function mutations in the Survival of Motor Neuron (SMN) protein. In a C.elegans model we have identified suppressors of the loss of SMN phenotype and the resulting animals have a normal life span. We are interrogating the molecular pathways underlying this astounding phenotype.

 

Metabolism and neurodegeneration

Mitochondrial dysfunction is a universal feature of neurodegenerative disease and the impairment in ATP production and enhanced elaboration of reactive oxygen species leads to the activation of AMP-dependent protein kinase (AMPK). Active AMPK turns off energy consuming processes and activated energy producing processes. While a priori this rewiring of intermediary metabolism should be a benefit, it in fact is injurious to neurons. We are exploring why rewiring of metabolism damages neurons and the extent to which abrogating specific AMPK actions can be leveraged into a therapy

Lim, M., Selak, M., Xiang, Z., Krainc, D., Neve, R., Kraemer, B., Watts, J. and Kalb, R. Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease J. Neuroscience 32(3):1123-1141, 2012

Boccitto, M, Lamitina, T and Kalb, R. Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans. PloS One 7(3) e33494 (2012)

Lim,M.A, Bence,K.K., Sandesara, I., Andreux, P. Auwerx, J., Ishibashi, J., Seale, P. and Robert G. Kalb, R. G. Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis Hum. Mol. Genet. doi:10.1093/hmg/ddu214 (2014)

 

RAN translation toxicity

Hexanucleotide repepat expansion (HRE) in an intron of the C9ORF72 gene is a major cause of ALS. One mechanism of toxicity originated in non-ATG, repeat associated translation of the HRE leading to the generation of toxic diamino acid peptide. We are modeling this in vitro and have identified a new cellular mechanism of toxicity that may be amenable to therapeutic intervention

 

Role of ARF GTP’ases during neurodegeneration

ARF GTP’ases are molecular switches that are involved in a variety of cell biological processes such as membrane traffic, lipid droplet formation and actin remodeling. We have found that inhibiting ARF action is neuroprotective in a variety of model systems. We are exploring the specific cell biological process that ARF inhibition impacts to promote the clearance of misfolded proteins

Zhai, J.,Zhang, L., Mojsilovic-Petrovic, J., Jian, X., Thomas, J.,Homma, K., Schmitz, A., Famulok, M., Ichijo, H., Argon, Y., Randazzo, P.A. and Kalb, R. G. Inhibition of cytohesins protects against genetic models of motor neuron disease. J. Neuroscience 35:9088-9105 (2015)

Recent Papers

Molecular and Cellular Neuroscience

Structurefunction analysis of SAP97, a modular scaffolding protein that drives dendrite growth

Read / download

The Journal of Neuroscience

Inhibition of Cytohesins Protects against Genetic Models of
Motor Neuron Disease

Read / download

The Journal of Neuroscience

Loss of RAD-23 Protects Against Models of Motor Neuron
Disease by Enhancing Mutant Protein Clearance

Read / download

Human Molecular Genetics

Genetically altering organismal metabolism
by leptin-deficiency benefits a mouse model
of amyotrophic lateral sclerosis

Read / download

Grants

Active

  • 1R21NS087077-01 “ERAD genes that suppress neurodegeneration”  9/1/2014 – 3/31/2016.
  • R01 NS095746-01 “AMPK, metabolism and ALS” 04/01/2016 – 03/31/21.
  • R21NS093439 “Cytohesins, ARF GTP’ases and neurodegeneration  09/01/16 – 08/31/18.

Pending

  • R21NS095310-01A1 “Mitochondrial unfolded protein response in models of Amyotrophic Lateral Sclerosis” 07/01/2016 – 06/30/2018.
  • 1R01NS099123-01 “Neurobiology of Cysteine Rich interactor of PDZ3” 9/1/2016 – 8/31/2021.
  • ALS Association “RAN peptide inhibition of proteasomal flux”

Contact Us

The Children’s Hospital of Philadelphia
Abramson Research Center, Room 814
3615 Civic Center Boulevard
Philadelphia, PA 19104

Phone
(215) 590 – 0691

Fax
(267) 426 – 5165

Email
kalb@email.chop.edu

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