High resolution analyses of FAM205C and FAM227A in sperm perinuclear theca and mitochondrial formation and function

Active Project Grant Awarded Last action

Award ID
F32HD123515
Recipient
Awarding agency
Obligated
$79,348

Award facts

Assistance listing
93.865 Child Health and Human Development Extramural Research
Completion date 0% complete
Place of performance
New Haven, CT 06510, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Male infertility is a prevalent issue affecting a significant portion of couples worldwide, yet its molecular causes are not well understood. There exists a common but unexplained observation in both mouse and human sperm that mutations affecting proteins exclusively localized within the sperm head leads to sperm motility defects as well. Thus, elucidating the molecular assembly and function of the sperm apparatus is essential for advancing reproductive medicine to explain this seemingly contradicting observation. This proposed fellowship project aims to uncover molecular mechanisms underlying male infertility, with a focus on elucidating the roles of the uncharacterized proteins FAM205C and FAM227A in sperm biology. Preliminary data suggests that FAM205C localizes to the perinuclear theca (PT) region of the sperm head, specifically the inner acrosomal membrane. FAM205C-/- and FAM227A-/- male mice are subfertile and possess sperm hyperactivation defects. Interestingly, both FAM205C-/- and FAM227A-/- sperm proteomes possess a unique proteomic signature of aberrantly expressed PT and mitochondrial proteins compared to WT sperm. The primary goal of this proposed research is to investigate the functions of FAM205C and FAM227A in sperm biology, focusing on their contributions to the stability of the PT and to mitochondrial activity. This project aims to equip the trainee with the essential skills required to achieve their aspiration of leading an independent research team. The project is divided into three aims. Aim 1: define the roles of FAM205C and FAM227A in PT assembly and stability. This includes understanding their localization and interactions with other PT proteins, as well as the implications of their loss on acrosome stability and nuclear integrity. Aim 2: determine the contribution of FAM205C and FAM227A to mitochondrial function in sperm. This will involve examining the effects of loss of FAM205C and FAM227A on sperm mitochondrial activity, ATP production, membrane potential, and oxidative stress. Aim 3: elucidate the in-cell structure of protein complexes involved in the PT and mitochondrial electron transport chain. Advanced electron microscopy techniques will be employed to gain structural insights into the role of FAM205C and FAM227A in biogenesis and function of these sperm structures. The expected outcomes of this research include the identification of novel molecular pathways linking PT stability and mitochondrial function to sperm motility and fertility. IT aims to identify new diagnostic markers and potential therapeutic targets for male infertility. The project is innovative due to its focus on deorphanizing FAM205C and FAM227A, defining a novel communication pathway, and using cutting-edge imaging techniques for detailed structural analysis. The wide variety of new skills gained from completion of this fellowship training will provide an exemplary foundation for future leadership of a laboratory in academia.

Quick answers

Who received award F32HD123515?

F32HD123515 was awarded to Yale Univ by National Institute of Child Health and Human Development (National Institutes of Health) on February 1, 2027.

How much is award F32HD123515 worth?

$79,348 has been obligated on F32HD123515.

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