# URM Student supplement  - R01 NS126504 SSingh

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $13,461

## Abstract

Project Summary/ Abstract
Though synapses are formed between neurons, these structures are contacted with, ensheathed, and
regulated by astrocytes. Period of neuronal synaptic connectivity and that of astrocyte maturation overlaps in
developing brain. Neuronal signals instruct astrocyte differentiation and morphological maturation whereas
astrocytes provide metabolic and trophic factors to support neuronal survival and growth. However, molecular
mechanisms and signals that regulate neuron-astrocyte interactions and their role in neuronal circuit assembly
and functions are largely unknown. We and others have previously shown that astrocytes modulate specific
neural circuit formation, function and plasticity by several secreted proteins including hevin (SPARCL1),
thrombospondins (TSPs), glypicans and norrin. While hevin is needed for assembly and plasticity of VGlut2+
(vesicular glutamate transporter 2) thalamocortical connections, TSPs facilitate VGlut1+ synapse formation.
Intriguingly, expression of these synaptogenic proteins is developmentally regulated and are also altered in brain
pathologies. Although a significant amount of research has been done to identify the neuronal receptors and
mechanism of synapse formation by astrocyte-secreted synaptogenic factors SPARCL1 and TSPs, we do not
know the signals and mechanisms that regulate their expression in astrocytes.
 We have recently found that neuronal contact stimulates expression of SPARCL1 and TSP4 via Sphingosine-
1-Phosphate (S1P)-S1P Receptor 1 (S1PR1). We also found that S1PR1 is primarily expressed by astrocytes
and is localized to the fine astrocytic processes near and around the synapses and drives astrocyte
morphological complexity and morphogenesis. Although, S1P-S1PR signaling is a drug target for many
neurological disorders, its fundamental role in neuron-glia interactions and neuronal circuit assembly is not
known. Our proposed studies will provide novel insight into the neuron-astrocyte bidirectional communication
through S1P-S1PR1 axis in establishing synaptic connectivity and functions. Our detailed mechanistic studies
will identify new signaling pathway downstream of S1P-S1PR1 axis in regulating calcium dynamics, glutamate
sensing and expression of SPARCL1 and TSP4 in astrocytes. These studies will also advance our knowledge
of how neurons regulate astrocyte development, morphogenesis and function. Moreover, these studies will
decipher the mechanistic link between levels of S1P and the expression of SPARCL1 and TSP4 and clarify on
the fundamental role of S1P/S1PR1 axis in the developing and diseased brain. This proposal thus is poised to
provide novel mechanisms of targeting S1P/S1PR1 axis in alleviating neuropathologies.

## Key facts

- **NIH application ID:** 11090169
- **Project number:** 3R01NS126504-02S1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Sandeep Kumar Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $13,461
- **Award type:** 3
- **Project period:** 2022-09-27 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11090169

## Citation

> US National Institutes of Health, RePORTER application 11090169, URM Student supplement  - R01 NS126504 SSingh (3R01NS126504-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11090169. Licensed CC0.

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