Photo of Phyllis A. Shaw

Phyllis A. Shaw

  • ASSOCIATE PROFESSOR Medical Education
  • ASSOCIATE PROFESSOR Neuroscience
  • ASSOCIATE PROFESSOR Neurology
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Training Areas

Education

  • MS, Ph.D., University of Texas Graduate School of Biomedical Sciences
    Medical Genetics, Molecular Biology, Biochemistry

Research

Cystatin C derived peptide as a new tool (in fight) against Alzheimer’s disease.

Dr. Shaw has a long-standing research interest in the molecular biology of cystatins, inhibitors of the proteolytic enzymes cathepsins (funded by NIH over 20 years to investigate the nervous system control of salivary gland cystatins).  She has also served as the histology course Director in our Icahn School of Medicine for 22 years. Participation in the medical school curriculum brought into sharp focus the need to utilize her basic science expertise and findings to bear on a clinically relevant problem. Dr. Shaw’s knowledge of cystatins and the developing awareness that cystatin C might be important in Alzheimer’s disease provided an impetus for her studies using a Cystatin C derived peptide as a new therapeutic tool in the fight against Alzheimer’s disease.  Cystatin C is expressed in the brain but its expression appears to wane prior to onset of Alzheimer’s disease. Cathepsin B, a cysteine proteinase present in the brain can degrade Aβ yet, paradoxically, over expression of its inhibitor, cystatin C (CysC), rather than increasing, lowers Aβ brain deposition in AD mouse models. This is likely due to a specific portion of the CysC protein (aa101-117) that binds Aβ (aa17-28), distinct from its proteinase-inhibitory sequence. Thus, cystatin C exerts dual effects through two separate parts of the molecule: a detrimental effect due to inhibition of cathepsins, and a therapeutic effect by prevention of amyloid β (Aβ) fibril formation. CysC peptide (aa101-117) interaction inhibits fibril formation in vitro and, possibly, Aβ oligomerization, and neurotoxicity in vivo. Dr. Shaw hypothesized that a synthetic peptide representing the aa101-117 sequence of CysC (CysC-AβBP) will prevent formation of soluble oAβ and Aβ plaques, and will slow AD progression; the peptide will not interfere with the Aβ-degrading cathepsin B function.  She developed the idea that for a successful anti-Alzheimer therapy, the two cystatin C activities will have to be separated and methods developed to generate sufficiently high concentrations of the Aβ-blocking activity.  Using synthetic CysC-AβBP delivered intranasally produced very promising results ; in mice developing Alzheimer’s disease, it reduced plaque formation in the hippocampus by 72% and in the neocortex by 64%.   The Shaw lab considers it an exceptional opportunity to be able to apply the knowledge gained over a long scientific career to a public health problem with such serious ramifications. Alzheimer’s disease (AD) is a progressive, incurable neurodegenerative disease that afflicts more than 5 million people in the U.S. today and has devastating socio-economic consequences. This novel approach has the potential of improving the quality of life for millions affected by Alzheimer’s disease and their families, and to reduce the staggering financial burden on the health care system.

Publications

Chaparro O, Yu WA, Shaw P. The Effect of Sympathectomy on Isoproterenol-Induced Expression of the Cysteine Proteinase Inhibitor Gene, Cystatin S, in Rat Submandibular Glands. Archs. Oral Biol. 1997; 42(10/11): 743-754.

Yu WA, Chaparro O, Shaw P. Isoproterenol-induced Expression of the Cystatin S Gene in Submandibular Glands of Parasympathectomized Rats. Brain Res Mol Brain Res 1998; 9: 136-146.

Shaw P, Chaparro O. Cystatin S: Molecular Biology and Sympathetic Innervation. 'The Salivary Gland-Cervical Sympathetic Trunk Axis: Participation in Homeostatic Regulation' . Biomedical Reviews 1998; 9: 33-46.

Chaparro O, Yu WA, Shaw P. Effect of Sympathetic Innervation on Isoproterenol-induced Cystatin S Gene Expression in Rat Submandibular Glands during Early Development. Dev Neurosci 1998; 20: 65-73.

Shaw P, Chaparro O. The 5'-Flanking Sequence and Regulatory Elements of the Cystatin S Gene. Biochem. and Biophys. Res. Commun. 1999; 261: 705-711.

Shaw PA, Yu WH. Autonomic Regulation of Cystatin S Gene Expression in Rat Submandibular Glands. Auton Neurosci 2000; 83: 49-57.

Shaw PA, Yu WH. Sympathetic and Parasympathetic Regulation of Cystatin S Gene Expression in Rat Submandibular Glands. Life Sci 2001; 70: 301-313.

Shaw PA, Zhang X, Russo AF, Amendt BA, Henderson S, Williams V. Homeobox Protein, Hmx, in Postnatally Developing Rat Submandibular Glands. J Histochem Cytochem 2003; 51: 385-396.

Industry Relationships

Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

Dr. Shaw did not report having any of the following types of financial relationships with industry during 2012 and/or 2013: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.

Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

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Address

Annenberg Building Floor 18 Room 18-08
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Address

Annenberg Building Floor 18 Room 18-08
1468 Madison Avenue
New York, NY 10029