SBIR-STTR Award

Kinase Inhibitors against Neurodegeneration
Award last edited on: 4/29/19

Sponsored Program
STTR
Awarding Agency
NIH : NINDS
Total Award Amount
$235,528
Award Phase
1
Solicitation Topic Code
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Principal Investigator
Gary S Lynch

Company Information

Thuris Corporation

101 Theory Drive Suite 250
Irvine, CA 92612
   (949) 417-4623
   khoffman@thuris.com
   www.thuris.com

Research Institution

University of California - Irvine

Phase I

Contract Number: 1R41NS047759-01
Start Date: 00/00/00    Completed: 00/00/00
Phase I year
2004
Phase I Amount
$235,528
Niemann-Pick type C (NPC) is a rare and fatal neurovisceral storage disorder that is currently untreatable, in most cases (95%), NPC is caused by mutations of the NPC1 gene, which encodes a glycoprotein playing an important role in cholesterol transport. NPC brains are also characterized by axonal abnormalities, neurofibrillary tangles (NFTs), and progressive neurodegeneration. The mechanisms leading to pathology in NPC are not well understood, although altered cholesterol metabolism in NPC mutant cells leads to axonal and neuronal degeneration as well as to hyperphosphorylation of the tau protein, which is the major component of NFTs. Interestingly, the NFTs observed in NPC and in Alzheimer's disease (AD) are chemically and morphologically indistinguishable and, in AD, they correlate with the severity of dementia. In brains from NPC1-/- mice, the activity of several protein kinases is altered and these alterations may result in tau modifications and neuronal death. In particular, the activities of cyclin-dependent kinase 5 (cdk5) and mitogen-activated protein kinase (MAPK) are elevated in NPCl-defective cells. This suggests that increased activity of selected protein kinases plays a critical role in NPC pathogenesis. The proposed experiments are directed at the following questions: (1) What are the contributions of cdk5, GSK3-beta, and MAP kinases to tau hyperphosphorylation and NFT formation? (2) What are the contributions of these kinases in the development of pathology taking place in NPC1-/- mice? Therefore, our specific aims are to (i) determine the effects of a variety of protein kinase inhibitors on a well established in vitro model of tau hyperphosphorylation and NFT formation using cultured hippocampal slices from ApoE-/- mice, (ii) test the effects of the most potent inhibitors of each class of protein kinases obtained in Aim 1 on a similar model that uses cultured hippocampal and cerebellar slices from NPC1-/- mice, and (iii) test the hypothesis that selected protein kinase inhibitors will prevent tau hyperphosphorylation, neuronal degeneration, microglial and astroglial reaction, and motor deficits in NPC1-/- mice in vivo. The proposed studies have the potential to (i) identify the pathway responsible for tau hyperphosphorylation and tangle formation, (ii) provide critical information concerning the role of specific protein kinases in other pathological manifestations of NPC disease, and (iii) open the way to broad-based drug discovery programs directed at essential aspects of NPC and AD.

Thesaurus Terms:
disease /disorder prevention /control, enzyme activity, neural degeneration, pathologic process, phosphorylation, protein kinase inhibitor, tau protein Niemann Pick disease, cyclin dependent kinase, glycogen synthase, mitogen activated protein kinase, neurofibrillary tangle, serine threonine protein kinase SDS polyacrylamide gel electrophoresis, immunocytochemistry, laboratory mouse, polymerase chain reaction, tissue /cell culture, western blotting

Phase II

Contract Number: ----------
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
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Phase II Amount
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