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Functional mechanisms underlying Dystroglycan-dependent and independent roles of protein O-mannosylation in the nervous system

Award Number: R01NS099409
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The main objective of this project is to elucidate functional mechanisms underlying regulation of the nervous system by protein O-mannosylation (POM). POM is an essential type of O-glycosylation that has a profound effect on the development and physiology in a broad range of animals, from Drosophila to humans. Although the spectrum of biological functions affected by POM is wide, so far the only well-studied target of POM is Dystroglycan (Dg). Defects in POM modifications of Dg result in severe muscular dystrophies called dystroglycanopathies. Pathomechanisms associated with POM defects are complex and remain poorly understood, particularly in the nervous system. Recent studies suggested that POM modification affects functions of many proteins, which contributes to pathogenic mechanisms of dystroglycanopathies. However, functions of POM on proteins besides Dg are largely unknown. The complexity of glycosylation and limitations of in vivo approaches create significant challenges for studying POM in mammalian organisms. Here we propose a multidisciplinary project that uses advantages of Drosophila model, including powerful arsenal of genetic approaches, simplified glycosylation and experimental amenability of POM and Dg mutants, to elucidate molecular and cellular mechanisms of Dg- dependent and Dg-independent functions of POM, with the focus on the nervous system and neuromuscular development and physiology. Our preliminary studies suggested that Receptor Protein Tyrosine Phosphatases (RPTPs) are functionally important POM targets and revealed that POM regulates coordinated muscle contractions by affecting communication between sensory neurons and the CNS. We will capitalize on these results while focusing on three specific aims: (1) To analyze the role of POM in regulation of sensory neurons and coordinated muscle contractions. Using live imaging techniques combined with genetic and neurobiological approaches, we will comprehensively investigate the role of POM in communication between sensory neurons, CNS cells and muscles. (2) To investigate the effect of POM on RPTP function. Using in vivo and in vitro approaches, we will investigate how POM affects functions RPTPs at molecular, cellular, and organismal levels. (3) To reveal new molecular targets of POM and elucidate their function in the nervous system. We will use glycoproteomic approaches to identify proteins with POM modifications. We will analyze functions of POM on novel targets in vivo, focusing on proteins that function in the nervous system. We anticipate that this project will establish new paradigms of POM-mediated regulation of the nervous system and will elucidate new evolutionarily conserved, Dg- dependent and independent mechanisms of POM functions, which will shed light on pathomechanisms of human diseases associated with POM abnormalities.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$1 )
2025	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/12/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $310,582 )
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/6/2021	NON-COMPETING CONTINUATION	$310,582
														Subtotal = $310,582

Issue Date FY: 2020 ( Subtotal = $311,261 )
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/1/2020	NON-COMPETING CONTINUATION	$311,261
														Subtotal = $311,261

Issue Date FY: 2019 ( Subtotal = $311,907 )
2019	2019	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/24/2019	NON-COMPETING CONTINUATION	$311,907
														Subtotal = $311,907

Issue Date FY: 2018 ( Subtotal = $312,524 )
2018	2018	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/27/2018	NON-COMPETING CONTINUATION	$312,524
														Subtotal = $312,524

Issue Date FY: 2017 ( Subtotal = $313,111 )
2017	2017	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/8/2017	NEW	$313,111
														Subtotal = $313,111

Grand Total All Awards = $1,559,384

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Functional mechanisms underlying Dystroglycan-dependent and independent roles of protein O-mannosylation in the nervous system

Award Number: R01NS099409

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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