# GLYCOSPHINGOLIPID METABOLISM AND MENTAL RETARDATION

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 1994 · $237,685

## Abstract

The broad, long-term objectives are to understand the role of glycolipids
(glycoshingolipids (GSL) and inositolphosphoglycerides) in normal nervous
function and the pathogenic processes involving them which lead to mental
retardation.  To achieve this goal we will use cultured cells which express
either neural-specific properties (neurons, neurotumor hybrid cell lines,
oligodendrocytes), or inherited metabolic defects (fibroblasts), in
conjunction with metabolic studies, enzyme assays, specific antibodies, and
cDNA transfection of specific proteins.  The two major Specific Aims are:

1) To understand how receptors are coupled to the activation of
phospholipase C (PLC) and the hydrolysis of phosphoinositides, and how this
system is regulated by protein kinase A, protein kinase C, glycolipids and
derived free sphingosine bases.  a) We will focus on low molecular weight
GTP-binding proteins such as rap1b, their turnover, phosphorylation,
membrane association and coupling to receptors and PLC.  We will study
three cell lines in which receptor-PLC coupling seems to be regulated
differently, namely NCB-20, WEHI-3 and human oligodendroglioma cells.  b)
We will determine how sphingosines activity, and how they could
physiologically regulate both PK-C and PLC activity, and how their re-
palmitoylation could be related to the acylation/deacylation of bioactive
proteins such as GAP-43.

2) To elucidate the role of glycosphingolipids in the mechanism of certain
types of neural cell injury.  a) We will study hypoxia in neonatal rat
oligodendrocytes since hypoxia initially restricts O2 for 2-hydroxy fatty
acid GSL synthesis and depletes ATP levels sufficiently to disrupt inter-
organellar translocation and phosphorylation of key myelin proteins.  b)
Since high titers of anti-GM1, GM2, and GD1b antibodies in humans appear to
selectively destroy motor neuron-muscle synaptic contacts and cause motor
neuron disease, we will study the role of gangliosides in regulating Ca2+,
second messengers and synaptogenesis.  c) We will determine the point
mutations in the beta-Hex gene in patients with partial deficiency of the
GM2-ganglioside degrading enzyme N-acetyl-beta-D-glucosaminidase (beta-Hex)
in order to understand more about beta-Hex, how enzymes degrade GSL, and
how better remedial therapy might be designed.

## Key facts

- **NIH application ID:** 2194973
- **Project number:** 5R01HD006426-23
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **SAM.gov UEI:** ZUE9HKT2CLC9
- **Principal Investigator:** Glyn Dawson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $237,685
- **Award type:** 5
- **Project period:** 1978-06-01 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2194973

## Citation

> US National Institutes of Health, RePORTER application 2194973, GLYCOSPHINGOLIPID METABOLISM AND MENTAL RETARDATION (5R01HD006426-23). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2194973. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*