Michael L. Shelanski, M.D., Ph.D.

Research Summary
Cytoskeleton and neural development

We are using a combination of cell biological and molecular biological approaches, including anti-sense technology, to study the function of two proteins: the intermediate filament peripherin and the high molecular weight form of the microtubule associated protein tau. These proteins are characteristic of the cytoskeleton of the peripheral neuron. We are interested in why there are differences between the central and peripheral cytoskeleton and whether these differences are related to the greater regenerative potential of peripheral neurons. To aid in this effort we have set up a model "axon" using baculovirus expression and insect SF9 cells to assess interactions between specific cytoskeletal components.

A related series of studies is investigating the mechanism by which astrocytes and neurons initiate the formation of long asymmetric processes. Our approach has shown that process formation in the astrocyte is inhibited by the cortical actin network and favored by the assembly of microtubules. This equilibrium is controlled by the myosin light chain kinase acting on the myosin light chain and on destrin, an actin-severing protein. These studies utilize a variety of cell biology approaches including biochemistry, EM, optical imaging and antisense oligonucleotides. Other research in the laboratory is on the role of cytokines, specifically IL-1, on the development of cytoskeletal changes in Alzheimer's disease.

1. Troy CM, Shelanski ML. Caspase-2 redux. Cell Death Differ. 2003 Jan;10(1):101-7.

2. Troy CM, Rabacchi SA, Hohl JB, Angelastro JM, Greene LA, Shelanski ML. Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. J Neurosci. 2001 Jul 15;21(14):5007-16. Erratum in: J Neurosci 2001 Aug 15;21(16):1b.

3. Troy CM, Rabacchi SA, Xu Z, Maroney AC, Connors TJ, Shelanski ML, Greene LA. beta-Amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation. J Neurochem. 2001 Apr;77(1):157-64.

4. Angelastro JM, Klimaschewski L, Tang S, Vitolo OV, Weissman TA, Donlin LT, Shelanski ML, Greene LA. Identification of diverse nerve growth factor-regulated genes by serial analysis of gene expression (SAGE) profiling. Proc Natl Acad Sci USA. 2000 Sep 12;97(19):10424-9.

5. Park DS, Morris EJ, Bremner R, Keramaris E, Padmanabhan J, Rosenbaum M, Shelanski ML, Geller HM, Greene LA. Involvement of retinoblastoma family members and E2F/DP complexes in the death of neurons evoked by DNA damage. J Neurosci. 2000 May 1;20(9):3104-14.

6. Troy CM, Rabacchi SA, Friedman WJ, Frappier TF, Brown K, Shelanski ML. Caspase-2 mediates neuronal cell death induced by beta-amyloid.
J Neurosci. 2000 Feb 15;20(4):1386-92.

1. Pathology and Biology of Neurodegenerative Disease
The first portion of work proposed will examine the role of alpha beta on the regulation of cAMP levels and investigate the mechanism of alpha beta Down regulation of PKA activity. Emphasis will be on the regulation of levels of the regulatory subunits of PKA. Experiments of APP Tg mice will examine the mechanism of LTP inhibition in the animals and determine if rolipram and forskalin reverse this inhibition. The second portion of the application examines the role of caspase 2 in cellular responses to alpha beta and will explore the issue of whether caspase 2 is necessary for the synaptic loss in APP Tg mice by crossing these animals with caspase 2 null mice.
National Institute of Neurological Disorders and Stroke
6/1/1989-3/31/2008

2. Alzheimer's Disease Research Center at Columbia University
The Alzheimer's Disease Research Center (ADRC) at Columbia University was established to encourage and integrate research on the causes of Alzheimer's Disease (AD) and related age-related neurodegenerative diseases and to foster the development of improved diagnosis, prevention and treatment of these conditions. Dr. Shelanski is principal investigator of the ADRC.
National Insitute on Aging
9/1989-5/2005

3. Medical Scientist Training Program
The Columbia University M.D./Ph.D. program, a joint endeavor of the Graduate School of Arts and Sciences and the Faculty of Medicine (College of Physicians & Surgeons), was established in 1973 to train physician-scientists for academic careers in biomedical research and teaching. The program admits students who have demonstrated outstanding intellectual achievements, capability in research and strong motivation for an academic career. Students earn the Ph.D. degree by fulfilling the rigorous requirements of the Graduate School of Arts and Sciences and they earn the M.D. degree in a medical curriculum which emphasizes both depth in the basic sciences and a comprehensive grounding in the clinical sciences.
National Institute of General Medical Sciences
11/1/1976-6/30/2007

Alzheimer's disease, amyloid protein, cyclic AMP, cysteine endopeptidase, enzyme activity, long term potentiation, neural degeneration, neuropathology, protein kinase A, cAMP response element binding protein, cell differentiation, cell growth regulation, developmental neurobiology, forskolin, glial fibrillary acidic protein, myosin light chain kinase, nervous system disorder chemotherapy, neuron, synapse,clinical research, laboratory mouse, polymerase chain reaction, serial analysis of gene expression, terminal nick end labeling, tissue /cell culture