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Ion Channel Pharmacology for Pain and Epilepsy

Award Number: R35NS127216
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2030

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Ion Channel Pharmacology for Pain and Epilepsy - Project Summary/ Abstract The proposed work will integrate two long-standing lines of research in the laboratory. One is to understand is to understand how the many types of ion channels present in a single neuron work together to regulate its firing pattern. In earlier grant periods, we focused on the individual gating behavior and functional roles of various kinds of calcium channels, sodium channels, and potassium channels in different kinds of mammalian neurons. More recently, we have tried to understand how the currents through the many kinds of channels in a given neuronal type interact, often in surprising ways, to control the firing pattern of the neuron. In a second line of research, we have characterized a variety of pharmacological agents that are targeted to voltage-dependent channels. Much of this work originally focused on finding peptide toxins and small molecules useful for separating components of current from specific channel types. Our goal now is to use our expanding knowledge about the differences in ion channel make-up of different kinds of neurons to rationally design novel compounds that can inhibit (or enhance) activity of specific kinds of neurons. Hypothesizing that it is no accident that many clinically- effective drugs act on multiple ion channels, we will attempt to design single compounds deliberately designed to inhibit or enhance specific combinations of voltage-dependent sodium, potassium, and calcium channels to differentially depress (or enhance) firing of specific neuronal types of interest, including primary nociceptors, hippocampal and cortical pyramidal neurons, various populations of cortical and hippocampal GABAergic neurons, and spinal cord motor neurons, in ways designed to have clinically beneficial effects. A key element of our approach is realizing that almost all small-molecule compounds targeted to voltage-dependent channels interact differentially with different gating states of the channels, resulting in complex dependence on voltage waveforms. Thus, differential inhibition of different neuronal types can be based on their different resting potentials, action potential shapes, and firing patterns as well as presence or absence of particular channel types being targeted. Our previous experience with a range of cell types, channel types, and channel-targeted drugs will provide a strong foundation for this effort.


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: 2026 ( Subtotal = $1,087,133 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/26/2026	NON-COMPETING CONTINUATION	$1,087,133
														Subtotal = $1,087,133

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	9/19/2025	OTHER REVISION	$0
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/8/2025	TERMINATION	$0
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,054,520 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/3/2024	NON-COMPETING CONTINUATION	$1,054,520
														Subtotal = $1,054,520

Issue Date FY: 2023 ( Subtotal = $1,087,133 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/10/2023	NON-COMPETING CONTINUATION	$1,087,133
														Subtotal = $1,087,133

Issue Date FY: 2022 ( Subtotal = $333,998 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/29/2022	NEW	$333,998
														Subtotal = $333,998

Grand Total All Awards = $3,562,784

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Ion Channel Pharmacology for Pain and Epilepsy

Award Number: R35NS127216

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2030

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